Method of using glucuronic acid or glucronolactone for treating wrinkles

ABSTRACT

Methods for visibly reducing a skin wrinkle and for reversing the effect of aging on human facial skin involving comprising topically applying to the wrinkle and/or affected facial skin glucuronic acid or glucuronolactone.

This application is a continuation, of application Ser. No. 08/135,841,filed Oct. 7, 1993, which is a continuation of U.S. application Ser. No.07/840,149, filed Feb. 24, 1992, now abandoned, which is a divisional ofU.S. application Ser. No. 07/393,749, filed on Aug. 15, 1989, now U.S.Pat. No. 5,091,171, which is a continuation-in-part of U.S. applicationSer. No. 06/945,680, filed on Dec. 23, 1986, now abandoned.

FIELD OF THE INVENTION

This invention relates generally to therapeutic treatment as well aspreventive measures for cosmetic conditions and dermatologic disordersby topical administration of amphoteric compositions or polymeric formsof alpha hydroxyacids, alpha ketoacids and related compounds. Weinitially discovered that alpha hydroxy or keto acids and theirderivatives were effective in the topical treatment of diseaseconditions such as dry skin, ichthyosis, eczema, palmar and plantarhyperkeratoses, dandruff, acne and warts.

We have now discovered that amphoteric compositions and polymeric formsof alpha hydroxyacids, alpha ketoacids and related compounds on topicaladministration are therapeutically effective for various cosmeticconditions and dermatologic disorders.

BRIEF DESCRIPTION OF THE PRIOR ART

In our prior U.S. Pat. No. 3,879,537 entitled "Treatment ofIchthyosiform Dermatoses" we described and claimed the use of certainalpha hydroxyacids, alpha ketoacids and related compounds for topicaltreatment of fish-scale like ichthyotic conditions in humans. In ourU.S. Pat. No. 3,920,835 entitled "Treatment of Disturbed Keratinization"we described and claimed the use of these alpha hydroxyacids, alphaketoacids and their derivatives for topical treatment of dandruff, acne,and palmar and plantar hyperkeratosis.

In our prior U.S. Pat. No. 4,105,783 entitled "Treatment of Dry Skin" wedescribed and claimed the use of alpha hydroxyacids, alpha ketoacids andtheir derivatives for topical treatment of dry skin. In our recent U.S.Pat. No. 4,246,261 entitled "Additives Enhancing Topical CorticosteroidAction" we described and claimed that alpha hydroxyacids, alphaketoacids and their derivatives, could greatly enhance the therapeuticefficacy of corticosteroids in topical treatment of psoriasis, eczema,seborrheic dermatitis and other inflammatory skin conditions.

In our more recent U.S. Pat. No. 4,363,815 entitled "Alpha Hydroxyacids,Alpha Ketoacids and Their Use in Treating Skin Conditions" we describedand claimed that alpha hydroxyacids and alpha ketoacids related to ororiginating from amino acids, whether or not found in proteins, wereeffective in topical treatment of skin disorders associated withdisturbed keratinization or inflammation. These skin disorders includedry skin, ichthyosis, palmar and plantar hyperkeratosis, dandruff,Darier's disease, lichen simplex chronicus, keratoses, ache, psoriasis,eczema, pruritus, warts and herpes.

In our most recent patent application Ser. No. 945,680 filed Dec. 23,1986 and entitled "Additives Enhancing Topical Actions of TherapeuticAgents" we described and claimed that incorporation of an alphahydroxyacid or related compound can substantially enhance therapeuticactions of cosmetic and pharmaceutical agents.

SUMMARY OF THE INVENTION

There is no doubt that alpha hydroxyacids, alpha ketoacids and relatedcompounds are therapeutically effective for topical treatment of variouscosmetic conditions and dermatologic disorders including dry skin, acne,dandruff, keratoses, age spots, wrinkles and disturbed keratinization.However, the compositions containing these acids may irritate human skinon repeated topical applications due to lower pH of the formulations.The irritation may range from a sensation of tingling, itching andburning to clinical signs of redness and peeling. Causes for suchirritation may arise from the following:

Upper layers of normal skin have a pH of 4.2 to 5.6, but thecompositions containing most alpha hydroxyacids or alpha ketoacids havepH values of less than 3.0. For example, a topical formulationcontaining 7.6% (1M) glycolic acid has a pH of 1.9, and a compositioncontaining 9% (1M) lactic acid has the same pH of 1.9. Thesecompositions of lower pH on repeated topical applications can cause adrastic pH decrease in the stratum corneum of human skin, and provokedisturbances in intercorneocyte bondings resulting in adverse skinreactions, especially to some individuals with sensitive skin.

Moreover, with today's state of the art it is still very difficult toformulate a lotion, cream or ointment emulsion which contains a freeacid form of the alpha hydroxyacid, and which is physically stable as acommercial product for cosmetic or pharmaceutical use.

When a formulation containing an alpha hydroxyacid or alpha ketoacid isreacted equimolarly or equinormally with a metallic alkali such assodium hydroxide or potassium hydroxide the composition becomestherapeutically ineffective. The reasons for such loss of therapeuticeffects are believed to be as follows:

The intact skin of humans is a very effective barrier to many naturaland synthetic substances. Cosmetic and pharmaceutical agents may bepharmacologically effective by oral or other systematic administration,but many of them are much less or totally ineffective on topicalapplication to the skin. Topical effectiveness of a pharmaceutical agentdepends on two major factors; (a) bioavailability of the activeingredient in the topical preparation and (b) percutaneous absorption,penetration and distribution of the active ingredient to the target sitein the skin. For example, a topical preparation containing 5% salicylicacid is therapeutically effective as a keratolytic, but that containing5% sodium salicylate is not an effective product. The reason for suchdifference is that salicylic acid is in bioavailable form and canpenetrate the stratum corneum, but sodium salicylate is not inbioavailable form and cannot penetrate the stratum corneum of the skin.

In the case of alpha hydroxyacids, a topical preparation containing 5%glycolic acid is therapeutically effective for dry skin, but thatcontaining 5% sodium glycollate is not effective. The same is true incase of 5% lactic acid versus 5% sodium lactate. The reason for suchdifference is that both glycolic acid and lactic acid are inbioavailable forms and can readily penetrate the stratum corneum, butsodium glycollate and sodium lactate are not in bioavailable forms andcannot penetrate the stratum corneum of the skin.

When a formulation containing an alpha hydroxyacid or alpha ketoacid isreacted equimolarly or equinormally with ammonium hydroxide or anorganic base of smaller molecule the composition still shows sometherapeutic effects for certain cosmetic conditions such as dry skin,but the composition has lost most of its potency for other dermatologicdisorders such as wrinkles, keratoses, age spots and skin changesassociated with aging.

It has now been discovered that amphoteric compositions containing alphahydroxyacids, alpha ketoacids or related compounds, and also thecompositions containing dimeric or polymeric forms of hydroxyacidsovercome the aforementioned shortcomings and retain the therapeuticefficacies for cosmetic conditions and dermatologic disorders. Theamphoteric composition contains in combination an amphoteric orpseudoamphoteric compound and at least ,one of the alpha hydroxyacids,alpha ketoacids or related compounds. Such amphoteric system has asuitable pH, and can release the active form of an alpha hydroxyacid oralpha ketoacid into the skin. The dimeric and polymeric forms of alpha,beta or other hydroxyacids in non-aqueous compositions have a moredesired pH than that of the monomeric form of the hydroxyacids. Thenon-aqueous compositions can be formulated and induced to release theactive form of hydroxyacids after the compositions have been topicallyapplied to the skin. The cosmetic conditions and dermatologic disordersin humans and animals, in which the amphoteric compositions containingthe dimeric or polymeric forms of hydroxyacids may be useful, includedry skin, dandruff, ache, keratoses, psoriasis, eczema, pruritus, agespots, lentigines, melasmas, wrinkles, warts, blemished skin,hyperpigmented skin, hyperkeratotic skin, inflammatory dermatoses, skinchanges associated with aging and as skin cleansers.

DETAILED DESCRIPTION OF THE INVENTION I. Amphoteric and PseudoamphotericCompositions

Amphoteric substances by definition should behave either as an acid or abase, and can be an organic or an inorganic compound. The molecule of anorganic amphoteric compound should consist of at least one basic and oneacidic group. The basic groups include, for example, amino, imino andguanido groups. The acidic groups include, for example, carboxylic,phosphoric and sulfonic groups. Some examples of organic amphotericcompounds are amino acids, peptides, polypeptides, proteins, creatine,aminoaldonic acids, aminouronic acids, lauryl aminopropylglycine,aminoaldaric acids, neuraminic acid, desulfated heparin, deacetylatedhyaluronic acid, hyalobiuronic acid, chondrosine and deacetylatedchondroitin.

Inorganic amphoteric compounds are certain metallic oxides such asaluminum oxide and zinc oxide.

Pseudoamphoteric compounds are either structurally related to trueamphoteric compounds or capable of inducing the same function when theyare incorporated into the compositions containing alpha hydroxyacids orketoacids. Some examples of pseudoamphoteric compounds are creatinine,stearamidoethyl diethylamine, stearamidoethyl diethanolamine,stearamidopropyl dimethylamine, quaternary ammonium hydroxide andquaternium hydroxide.

The amphoteric composition of the instant invention contains incombination an alpha hydroxyacid or alpha ketoacid and an amphoteric orpseudoamphoteric compound. There are two advantages of utilizing anamphoteric or the like compound in the therapeutic compositioncontaining an alpha hydroxy or ketoacid. These are (a) the overall pH ofthe composition is raised, so that the composition becomes less ornon-irritating to the skin and (b) some alpha hydroxy or ketoacidmolecules react with the amphoteric compound to form a quadruple ioniccomplex which acts as buffering system to control the release of alphahydroxy or ketoacid into the skin, therefore, eliminating the skinirritation and still retaining the therapeutic efficacies.

The following are some examples. 2-Hydroxyethanoic acid (glycolic acid)1M aqueous solution has pH 1.9. The pHs of compositions change to 3.0and 3.2 when arginine 0.5M and creatinine 0.5M respectively areincorporated into the formulations. 2-Hydroxypropanoic acid (lacticacid) 1M aqueous solution has pH 1.9. The pHs of compositions change to3.1 and 6.9 when arginine 0.5M and 1.0M respectively are incorporatedinto the formulations. 2-Methyl 2-hydroxypropanoic acid (methyllacticacid) 1M aqueous solution has pH 1.9. The pHs of compositions change to3.3, 3.4 and 3.2 when 0.5M each of arginine, creatinine and4-aminobutanoic acid respectively are incorporated into theformulations. 2-Hydroxybutane-1,4-dioic acid (malic acid) 1M aqueoussolution has pH 1.8, but the pH of the composition changes to 3.0 whencreatinine 0.5M is incorporated into the formulation.

Ideally, an amphoteric compound should contain both anionic and cationicgroups or functional groups capable of behaving both as an acid and abase. Although inorganic amphoteric compounds such as aluminum oxide,aluminum hydroxide and zinc oxide may be utilized, organic amphotericcompounds have been found to be more efficient in formulatingtherapeutic compositions of the instant invention.

Organic amphoteric and pseudoamphoteric compounds may be classified intothree groups, namely (a) amino acid type, (b) imidazoline and lecithinamphoterics and (c) pseudoamphoterics and miscellaneous amphoterics.

(a) Amino acid type amphoterics. Amphoteric compounds of amino acid typeinclude all the amino acids, dipeptides, polypeptides, proteins and thelike which contain at least one of the basic groups such as amino,imino, guanido, imidazolino and imidazolyl, and one of the acidic groupssuch as carboxylic, sulfonic, sulfinic and sulfate.

Glycine is a simple amphoteric compound which contains only one aminogroup and one carboxylic group. Lysine contains two amino groups and onecarboxylic group. Aspartic acid contains one amino group and twocarboxylic groups. Arginine contains one amino group, one guanido groupand one carboxylic group. Histidine contains one amino group, oneimidazolyl group and one carboxylic group. Taurine contains one aminogroup and one sulfonic group. Cysteine sulfinic acid contains one aminogroup, one carboxylic group and one sulfinic group. The amino group ofan amphoteric compound may also be substituted, such as in betaine whichis a glycine N,N,N-trimethyl inner salt.

Glycylglycine is a simple dipeptide which contains one free amino groupand one free carboxylic group. Glycylhistidine is also a dipeptide whichcontains one free amino group, one imidazolyl group and one freecarboxylic group.

The representative amphoteric compounds of amino acid type may be listedas follows: Glycine, alanine, valine, leucine, isoleucine, serine,threonine, cysteine, cystine, methionine, aspartic acid, asparagine,glutamic acid, glutamine, arginine, lysine, 5-hydroxylysine, histidine,phenylalanine, tyrosine, tryptophan, 3-hydroxyproline, 4-hydroxyprolineand proline.

The related amino acids include homocysteine, homocystine, homoserine,ornithine, citrulline, creatine, 3-aminopropanoic acid, theanine,2-aminobutanoic acid, 4-aminobutanoic acid, 2-amino-2-methylpropanoicacid, 2-methyl-3-aminopropanoic acid, 2,6-diaminopimelic acid,2-amino-3-phenylbutanoic acid, phenylglycine, canavanine, canaline,4-hydroxyarginine, 4-hydroxyornithine, homoarginine,4-hydroxyhomoarginine, β-lysine, 2,4-diaminobutanoic acid,2,3-diaminopropanoic acid, 2-methylserine, 3-phenylserine and betaine.

Sulfur-containing amino acids include taurine, cysteinesulfinic acid,methionine sulfoxide and methionine sulfone.

The halogen-containing amino acids include 3,5-diiodotyrosine, thyroxineand monoiodotyrosine. The imino type acids include pipecolic acid,4-aminopipecolic acid and 4-methylproline.

The dipeptides include for example, glycylglycine, carnosine, anserine,ophidine, homocarnosine, β-alanyllysine, β-alanylarginine. Thetripeptides include for example, glutathione, ophthalmic acid andnorophthalmic acid. Short-chain polypeptides of animal, plant andbacterial origin containing up to 100 amino acid residues includebradykinin and glucagon. The preferred proteins include for exampleprotamines, histones and other lysine and arginine rich proteins.

(b) Imidazoline and lecithin amphoterics. The amphoteric compounds ofimidazoline derived type are commercially synthesized from2-substituted-2-imidazolines obtained by reacting a fatty acid with anaminoethylethanolamine. These amphoterics include cocoamphoglycine,cocoamphopropionate, and cocoamphopropylsulfonate. The amphotericcompounds of lecithin and related type include for example, phosphatidylethanolamine, phosphatidyl serine and sphingomyelin.

(c) Pseudoamphoterics and miscellaneous amphoterics. Manypseudoamphoteric compounds are chemically related or derived from trueamphoterics. For example, creatinine is derived from creatine. Otherpseudoamphoteric compounds may include fatty amide amines such asstearamidoethyl diethylamine, stearamidoethyl diethanolamine andstearamidopropyl dimethylamine. Other pseudoamphoteric related compoundsinclude quaternary ammonium hydroxide and quaternium hydroxide.

In accordance with the present invention, the alpha hydroxyacid, thealpha ketoacids and the related compounds which are incorporated intoamphoteric or pseudoamphoteric compositions for cosmetic conditions anddermatologic disorders may be classified into three groups.

The first group is organic carboxylic acids in which one hydroxyl groupis attached to the alpha carbon of the acids. The generic structure ofsuch alpha hydroxyacids may be represented as follows:

    (Ra) (Rb) C (OH) COOH

where Ra and Rb are H, F, Cl, Br, alkyl, aralkyl or aryl group ofsaturated or unsaturated, isomeric or non-isomeric, straight or branchedchain or cyclic form, having 1 to 25 carbon atoms, and in addition Raand Rb may carry OH, CHO, COOH and alkoxy group having 1 to 9 carbonatoms. The alpha hydroxyacids may be present as a free acid or lactoneform, or in a salt form with an organic base or an inorganic alkali. Thealpha hydroxyacids may exist as stereoisomers as D, L, and DL forms whenRa and Rb are not identical.

Typical alkyl, aralkyl and aryl groups for Ra and Rb include methyl,ethyl, propyl, isopropyl, butyl, pentyl, octyl, lauryl, stearyl, benzyland phenyl, etc. The alpha hydroxyacids of the first group may bedivided into (1) alkyl alpha hydroxyacids, (2) aralkyl and aryl alphahydroxyacids, (3) polyhydroxy alpha hydroxyacids, and (4) polycarboxylicalpha hydroxyacids. The following are representative alpha hydroxyacidsin each subgroup.

(1) Alkyl Alpha Hydroxyacids

1. 2-Hydroxyethanoic acid (Glycolic acid, hydroxyacetic acid)

(H) (H) c (OH) COOH

2. 2-Hydroxypropanoic acid (Lactic acid)

(CH₃) (H) C (OH) COOH

3. 2-Methyl 2-hydroxypropanoic acid (Methyllactic acid)

(CH₃) (CH₃) C (OH) COOH

4. 2-Hydroxybutanoic acid

(C₂ H₅) (H) C (OH) COOH

5. 2-Hydroxypentanoic acid

(C₃ H₇) (H) C (OH) COOH

6. 2-Hydroxyhexanoic acid

(C₄ H₉) (H) C (OH) COOH

7. 2-Hydroxyheptanoic acid

(C₅ H₁₁ (H) C (OH) COOH

8. 2-Hydroxyoctanoic acid

(C₆ H₁₃) (H) C (OH) COOH

9. 2-Hydroxynonanoic acid

(C₇ H₁₅) (H) C (OH) COOH

10. 2-Hydroxydecanoic acid

C₈ H₁₇) (H) C (OH) COOH

11. 2-Hydroxyundecanoic acid

(C₉ H₁₉) (H) C (OH) COOH

12. 2 -Hydroxydodecanoic acid (Alpha hydroxylauric acid)

(C₁₀ H₂₁) (H) C (OH) COOH

13. 2-Hydroxytetradecanoic acid (Alpha hydroxymyristic acid)

(C₁₂ H₂₅) (H) C (OH) COOH

14. 2-Hydroxyhexadecanoic acid (Alpha hydroxypalmitic acid)

C₁₄ H₂₉) (H) C (OH) COOH

15. 2-Hydroxyoctadecanoic acid (Alpha hydroxystearic acid)

(C₁₆ H₃₄) (H) C (OH) COOH

16. 2-Hydroxyeicosanoic acid (Alpha hydroxyarachidonic acid)

(C₁₈ H₃₇) (H) C (OH) COOH

(2) Aralkyl And Aryl Alpha Hydroxyacids

1. 2-Phenyl 2-hydroxyethanoic acid (Mandelic acid)

(C₆ H₅) (H) C (OH) COOH

2. 2,2-Diphenyl 2-hydroxyethanoic acid (Benzilic acid)

(C₆ H₅) (C₆ H₅) C (OH) COOH

3. 3-Phenyl 2-hydroxypropanoic acid (Phenyllactic acid)

(C₆ H₅ CH₂) (H) C (OH) COOH

4. 2-Phenyl 2-methyl 2-hydroxyethanoic acid (Atrolactic acid)

(C₆ H₅) (CH₃) C (OH) COOH

5. 2-(4'-Hydroxyphenyl) 2-hydroxyethanoic acid (4-Hydroxymandelic acid)

(HO--C₆ H₄) (H) C (OH) COOH

6. 2-(4'-Chlorophenyl) 2-hydroxyethanoic acid (4-Chloromandelic acid)

(C₁ -C₆ H₄) (H) C (OH) COOH

7. 2-(3'-Hydroxy-4'-methoxyphenyl) 2-hydroxyethanoic acid

(3-Hydroxy-4-methoxymandelic acid)

(HO--,CH₃ O--C₆ H₃) (H) C (OH) COOH

8. 2-(4'-Hydroxy-3'-methoxyphenyl) 2-hydroxyethanoic acid

(4-Hydroxy-3-methoxymandelic acid)

(HO--,CH₃₀ -C₆ H₃) (H) C (OH) COOH

9. 3-(2'-Hydroxyphenyl) 2-hydroxypropanoic acid

3-(2'-Hydroxyphenyl) lactic acid!

HO--C₆ H₄ -CH₂ (H) C (OH) COOH

10. 3-(4'-Hydroxyphenyl) 2-hydroxypropanoic acid

3-(4'-Hydroxyphenyl) lactic acid!

HO--C₆ H₄ --CH₂ (H) C (OH) COOH

11. 2-(3',4'-Dihydroxyphenyl) 2-hydroxyethanoic acid(3,4-Dihydroxymandelic acid)

HO--,HO--C₆ H₃ (H) C (OH) COOH

(3) Polyhydroxy Alpha Hydroxyacids

1. 2,3-Dihydroxypropanoic acid (Glyceric acid)

(HOCH₂) (H) C (OH) COOH

2. 2,3,4-Trihydroxybutanoic acid (Isomers; erythronic acid, threonicacid)

HOCH₂ (HO)CH₂ (H) C (OH) COOH

3. 2,3,4,5-Tetrahydroxypentanoic acid (Isomers; ribonic acid, arabinoicacid, xylonic acid, lyxonic acid)

HOCH₂ (HO)CH₂ (HO)CH₂ (H) C (OH) COOH

4. 2,3,4,5,6-Pentahydroxyhexanoic acid (Isomers; allonic acid, altronicacid, gluconic acid, mannoic acid, gulonic acid, idonic acid, galactonicacid, talonic acid)

HOCH₂ (HO)CH₂ (HO)CH₂ (HO)CH₂ (H) C (OH) COOH

5. 2,3,4,5,6,7-Hexahydroxyheptanoic acid (Isomers; glucoheptonic acid,galactoheptonic acid etc.)

HOCH₂ (HO)CH₂ (HO)CH₂ (HO)CH₂ (HO)CH₂ (H) C (OH) COOH

(4) Polycarboxylic Alpha Hydroxyacids

1. 2-Hydroxypropane-1,3-dioic acid (Tartronic acid)

HOOC (H) C (OH) COOH

2. 2-Hydroxybutane-1,4-dioic acid (Malic acid)

HOOC CH₂ (H) C (OH) COOH

3. 2,3-Dihydroxybutane-1,4-dioic acid (Tartaric acid)

HOOC (HO)CH (H) C (OH) COOH

4. 2-Hydroxy-2-carboxypentane-1,5-dioic acid (Citric acid)

HOOC CH₂ C (OH)(COOH) CH₂ COOH

5. 2,3,4,5-Tetrahydroxyhexane-1,6-dioic acid (Isomers; saccharic acid,mucic acid etc.)

HOOC (CHOH)₄ COOH

(5) Lactone Forms

The typical lactone forms are gluconolactone, galactonolactone,glucuronolactone, galacturonolactone, gulonolactone, ribonolactone,saccharic acid lactone, pantoyllactone, glucoheptonolactone,mannonolactone, and galactoheptonolactone.

The second group Of compounds which may be incorporated into amphotericor pseudoamphoteric compositions for cosmetic conditions anddermatologic disorders, is organic carboxylic acids in which the alphacarbon of the acids is in keto form. The generic structure of such alphaketoacids may be represented as follows:

    (Ra) CO COO (Rb)

wherein Ra and Rb are H, alkyl, aralkyl or aryl group of saturated orunsaturated, isomeric or non-isomeric, straight or branched chain orcyclic form, having 1 to 25 carbon atoms, and in addition Ra may carryF, Cl, Br, I, OH, CHO, COOH and alkoxy group having 1 to 9 carbon atoms.The alpha ketoacids may be present as a free acid or an ester form, orin a salt form with an organic base or an inorganic alkali. The typicalalkyl, aralkyl and aryl groups for Ra and Rb include methyl, ethyl,propyl, isopropyl, butyl, pentyl, octyl, lauryl, stearyl, benzyl andphenyl, etc.

In contrast to alpha hydroxyacids the ester form of alpha ketoacids hasbeen found to be therapeutically effective for cosmetic and dermatologicconditions and disorders. For example, while ethyl lactate has a minimaleffect, ethyl pyruvate is therapeutically very effective. Although thereal mechanism for such difference is not known, we have speculated thatthe ester form of an alpha ketoacid is chemically and/or biochemicallyvery reactive, and a free acid form of the alpha ketoacid is released inthe skin after the topical application.

The representative alpha ketoacids and their esters which may be usefulin amphoteric or pseudoamphoteric compositions for cosmetic conditionsand dermatologic disorders are listed below:

1. 2-Ketoethanoic acid (Glyoxylic acid)

(H) CO COOH

2. Methyl 2-ketoethanoate

(H) CO COOCH₃

3. 2-Ketopropanoic acid (Pyruvic acid)

CH₃ CO COOH

4. Methyl 2-ketopropanoate (Methyl pyruvate)

CH₃ CO COOCH₃

5. Ethyl 2-ketopropanoate (Ethyl pyruvate)

CH₃ CO COOC₂ H₅

6. Propyl 2-ketopropanoate (Propyl pyruvate)

CH₃ CO COOC₃ H₇

7. 2-Phenyl-2-ketoethanoic acid (Benzoylformic acid)

C₆ H₅ CO COOH

8. Methyl 2-phenyl -2-ketoethanoate (Methyl benzoylformate)

C₆ H₅ CO COOCH₃

9. Ethyl 2-phenyl-2-ketoethanoate (Ethyl benzoylformate)

C₆ H₅ CO COOC₂ H₅

10. 3-Phenyl-2-ketopropanoic acid (Phenylpyruvic acid)

C₆ H₅ CH₂ CO COOH

11. Methyl 3-phenyl -2-ketopropanoate (Methyl phenylpyruvate)

C₆ H₅ CH₂ CO COOCH₃

12. Ethyl 3-phenyl-2-ketopropanoate (Ethyl phenylpyruvate)

C₆ H₅ CH₂ CO COOC₂ H₅

13. 2-Ketobutanoic acid

C₂ H₅ CO COOH

14. 2-Ketopentanoic acid

C₃ H₇ CO COOH

15. 2-Ketohexanoic acid

C₄ H₉ CO COOH

16. 2-Ketoheptanoic acid

C₅ H₁₁ CO COOH

17. 2-Ketooctanoic acid

C₆ H₁₃ CO COOH

18. 2-Ketododecanoic acid

C₁₀ H₂₁ CO COOH

19. Methyl 2-ketooctanoate

C₆ H₁₃ CO COOCH₃

The third group of compounds which may be incorporated into amphotericor pseudoamphoteric compositions for cosmetic and dermatologicconditions and disorders, is chemically related to alpha hydroxyacids oralpha ketoacids, and can be represented by their names instead of theabove two generic structures. The third group of compounds includeascorbic acid, quinic acid, isocitric acid, tropic acid, trethocanicacid, 3-chlorolactic acid, cerebronic acid, citramalic acid, agaricicacid, 2-hydroxynervonic acid, aleuritic acid and pantoic acid.

II. Dimeric and Polymeric Forms of Hydroxyacids

When two or more molecules of hydroxycarboxylic acids either identicalor non-identical compounds are reacted chemically to each other, dimericor polymeric compounds will be formed. Such dimeric and polymericcompounds may be classified into three groups, namely (a) acyclic ester,(b) cyclic ester and (c) miscellaneous dimer and polymer.

(a) Acyclic ester. The acyclic ester of a hydroxycarboxylic acid may bea dimer or a polymer. The dimer is formed from two molecules of ahydroxycarboxylic acid by reacting the carboxyl group of one moleculewith the hydroxy group of a second molecule. For example, glycolylglycollate is formed from two molecules of glycolic acid by eliminatingone mole of water molecule. Likewise, lactyl lactate is formed from twomolecules of lactic acid. When two molecules of differenthydroxycarboxylic acids are intermolecularly reacted, a different dimeris formed. For example, glycolyl lactate is formed by reacting thecarboxyl group of lactic acid with the hydroxy group of glycolic acid.The polymer is formed in a similar manner but from more than twomolecules of a hydroxycarboxylic acid. For example, glycoly glycolyglycollate is formed from three molecules of glycolic acid. Copolymer isformed from two or more than two different kinds of hydroxycarboxylicacids. For example, glycolyl lactyl glycollate is formed from twomolecules of glycolic acid and one molecule of lactic acid.

The acyclic ester of dimeric and polymeric hydroxycarboxylic acids maybe shown by the following chemical structure:

    H  --O--C(Ra)(Rb)--CO--!n OH

wherein Ra,Rb=H, alkyl, aralkyl ar aryl group of saturated orunsaturated, isomeric or non-isomeric, straight or branched chain orcyclic form, having 1 to 25 carbon atoms, and n=1 or any numericalnumber, with a preferred number of up to 200. Ra and Rb in monomer unit2, 3, 4 and so on may be the same or the different groups from that inmonomer unit 1. For example, Ra,Rb═H in monomer unit 1, and Ra═CH₃,Rb═Hin monomer unit 2 when n=2 is a dimer called lactyl glycollate, becausethe first monomer is glycollate unit and the second monomer is lacticacid unit. The hydrogen atom in Ra and Rb may be substituted by ahalogen atom or a radical such as a lower alkyl, aralkyl, aryl or alkoxyof saturated or unsaturated, isomeric or non-isomeric, straight orbranched chain or cyclic form, having 1 to 9 carbon atoms. The dimer andpolymer of a hydroxycarboxylic acid may be present as a free acid, esteror salt form with organic base or inorganic alkali.

The typical alkyl, aralkyl and aryl groups for Ra and Rb include methyl,ethyl, propyl, isopropyl, butyl, benzyl and phenyl. Representativeacyclic esters of hydroxycarboxylic acids which may be useful forcosmetic conditions and dermatologic disorders are listed below:

1. Glycolyl glycollate (Glycolic acid glycollate)

Ra,Rb═H in units 1 & 2, n=2

2. Lactyl lactate (Lactic acid lactate)

Ra=CH₃,Rb═H in units 1&2, n=2

3. Mandelyl mandellate

Ra=C₆ H₅,Rb═H in units 1 & 2, n=2

4. Atrolactyl atrolactate

Ra=C₆ H₅,Rb═CH₃ in units 1 & 2, n=2

5. Phenyllactyl phenyllactate

Ra=C₆ H₅ CH₂, Rb═H, in units 1 & 2, n=2

6. Benzilyl benzillate

Ra,Rb═C₆ H₅ in units 1 & 2, n=2

7. Glycolyl lactate

Ra═CH₃ in unit 1, Ra═H in unit 2, Rb═K in units 1 & 2, n=2

8. Lactyl glycollate

Ra═M in unit 1, Ra═CH₃ in unit 2, Rb═H in units 1 & 2,

9. Glycolyl glycolyl glycollate

Ra,Rb═H in units 1, 2 & 3, n=3

10. Lactyl lactyl lactate

Ra═CH₃, Rb═H in units 1, 2 & 3, n=3

11. Lactyl glycolyl lactate

Ra═CH₃ in units 1 & 3, Ra═H in unit 2, Rb═H in units 1, 2 & 3, n=3

12. Glycolyl glycolyl glycolyl glycollate

Ra,Rb═H in units 1, 2, 3 & 4, n=4

13. Lactyl lactyl lactyl lactate

Ra═CH₃, Rb═H in units 1, 2, 3 & 4, n=4

14. Glycolyl lactyl glycolyl lactyl glycollate

Ra═H in units 1, 3 & 5, Ra═CH₃ in units 2 & 4, Rb═H in units 1, 2, 3, 4& 5, n=5

15. Polyglycolic acid and polylactic acid

(b) Cyclic ester. The cyclic ester of a hydroxycarboxylic acid may alsobe a dimer or polymer, the most common type however, is a dimer form.The cyclic dimer may be formed from an identical monomer or differentmonomers. For example, glycolide is formed from two molecules ofglycolic acid by removing two molecules of water, and lactide is formedfrom two molecules of lactic acid in the same manner. The cyclic esterof dimeric and polymeric hydroxycarboxylic acids may be shown by thefollowing chemical structure:

     --O--C(Ra)(Rb)--Co--!n

wherein Ra,Rb═H, alkyl, aralkyl or aryl group of saturated orunsaturated, isomeric or non-isomeric, straight or branched chain orcyclic form, having 1 to 25 carbon atoms, and n=1 or any numericalnumber, however with a preferred number of 2. Ra and Rb in units 1, 2, 3and so on may be the same or the different groups. For example, inglycolide Ra and Rb are H in both units 1 & 2, but in lactoglycolide Rais H in unit 1, CH₃ in unit 2 and Rb is H in both units 1 & 2. Thehydrogen atom in Ra and Rb may be substituted by a halogen atom or aradical such as a lower alkyl, aralkyl, aryl or alkoxy of saturated orunsaturated, isomeric or non-isomeric, straight or branched chain orcyclic form, having 1 to 9 carbon atoms.

The typical alkyl, aralkyl and aryl groups for Ra and Rb include methyl,ethyl, propyl, isopropyl, butyl, benzyl and phenyl. Representativecyclic esters of hydroxycarboxylic acids which may be useful forcosmetic conditions and dermatologic disorders are listed below:

1. Glycolide

Ra,Rb═H, n=2

2. Lactide

Ra═CH₃, Rb═H in units 1 & 2, n=2

3. Mandelide

Ra═C₆ H₅, Rb═H in units 1 & 2, n=2

4. Atrolactide

Ra═C₆ H₅, Rb═CH₃ in units 1 & 2, n=2

5. Phenyllactide

Ra═C₆ H₅ CH₂, Rb═H in units 1 & 2, n=2

6. Benzilide

Ra,Rb═C₆ H₅ in units 1 & 2, n=2

7. Methyllactide

Ra,Rb═CH₃ in units 1 & 2, n=2

8. Lactoglycolide

Ra═H in unit 1, Ra═CH₃ in unit 2

Rb═H in units 1 & 2, n=2

9. Glycolactide

Ra═CH₃ in unit 1, Ra═H in unit 2

Rb═H in units 1 & 2, n=2

(c) Miscellaneous dimer and polymer. This group includes all the dimericand polymeric forms of hydroxycarboxylic acids, which can not berepresented by any one of the above two generic structures, such asthose formed from tropic acid, trethocanic acid and aleuritic acid. Whena hydroxycarboxylic acid has more than one hydroxy or carboxy group inthe molecule a complex polymer may be formed. Such complex polymer mayconsist of acyclic as well as cyclic structures.

The following hydroxycarboxylic acids have more than one hydroxy groups:glyceric acid, gluconic acid and gluconolactone, galactonic acid andgalactonolactone, glucuronic acid and glucuronolactone, ribonic acid andribonolactone, galacturonic acid and galacturonolactone, ascorbic acid,gulonic acid and gulonolactone, glucoheptonic acid andglucoheptonolactone. These polyhydroxycarboxylic acids can form complexpolymers with themselves or with other simple monohydroxymonocarboxylicacids.

The following hydroxycarboxylic acids have more than one carboxylgroups: malic acid, citric acid, citramalic acid, tartronic acid,agaricic acid and isocitric acid. These monohydroxypolycarboxylic acidscan also form complex polymers with themselves or with other simplehydroxycarboxylic acids.

The following hydroxycarboxylic acids have more than one hydroxy andmore than one carboxyl groups: tartaric acid, mucic acid and saccharicacid. These polyhydroxypolycarboxylic acids can form even more complexpolymers with themselves or with other hydroxycarboxylic acids.

III. Combination Compositions

Any cosmetic and pharmaceutical agents may be incorporated intoamphoteric or pseudoamphoteric compositions, or into compositionscontaining dimeric or polymeric forms of hydroxyacids with or withoutamphoteric or pseudoamphoteric systems to enhance therapeutic effects ofthose cosmetic and pharmaceutical agents to improve cosmetic conditionsor to alleviate the symptoms of dermatologic disorder. Cosmetic andpharmaceutical agents include those that improve or eradicate age spots,keratoses and wrinkles; analgesics; anesthetics; antiacne agents;antibacterials; antiyeast agents; antifungal agents; antiviral agents;antidandruff agents; antidermatitis agents; antipruritic agents;antiemetics; antimotion sickness agents; antiinflammatory agents;antihyperkeratolytic agents; antidryskin agents; antiperspirants;antipsoriatic agents; antiseborrheic agents; hair conditioners and hairtreatment agents; antiaging and antiwrinkle agents; antiasthmatic agentsand bronchodilators; sunscreen agents; antihistamine agents; skinlightening agents; depigmenting agents; vitamins; corticosteroids;tanning agents; hormones; retinoids; topical cardiovascular agents andother dermatologicals.

Some examples of cosmetic and pharmaceutical agents are clotrimazole,ketoconazole, miconazole, griseofulvin, hydroxyzine, diphenhydramine,pramoxine, lidocaine, procaine, mepivacaine, monobenzone, erythromycin,tetracycline, clindamycin, meclocycline, hydroquinone, minocycline,naproxen, ibuprofen, theophylline, cromolyn, albuterol, retinoic acid,13-cis retinoic acid, hydrocortisone, hydrocortisone 21-acetate,hydrocortisone 17-valerate, hydrocortisone 17-butyrate, betamethasonevalerate, betamethasone dipropionate, triamcinolone acetonide,fluocinonide, clobetasol propionate, benzoyl peroxide, crotamiton,propranolol, promethazine, vitamin A palmitate and vitamin E acetate.

IV. Specific Compositions For Skin Disorders

We have discovered that topical formulations or compositions containingspecific alpha hydroxyacids or alpha ketoacids, or related compounds aretherapeutically very effective for certain skin disorders withoututilizing any amphoteric or pseudoamphoteric systems. The alphahydroxyacids and the related compounds include 2-hydroxyethanoic acid,2-hydroxypropanoic acid, 2-methyl 2-hydroxypropanoic acid, 2-phenyl2-hydroxyethanoic acid, 2,2-diphenyl 2-hydroxyethanoic acid, 2-phenyl2-methyl 2-hydroxyethanoic acid and 2-phenyl 3-hydroxypropanoic acid.The alpha ketoacids and their esters include 2-ketopropanoic acid,methyl 2-ketopropanoate and ethyl 2-ketopropanoate. The mentioned skindisorders include warts, keratoses, age spots, acne, nail infections,wrinkles and aging related skin changes.

In general, the concentration of the alpha hydroxyacid, the alphaketoacid or the related compound used in the composition is a fullstrength to an intermediate strength, therefore the dispensing and theapplication require special handling and procedures.

If the alpha hdyroxyacid, or the alpha ketoacid or the related compoundat full strength (usually 95-100%) is a liquid form at room temperatureSuch as 2-hydroxypropanoic acid, 2-ketopropanoic acid, methyl2-ketopropanoate and ethyl 2-ketopropanoate, the liquid compound with orwithout a gelling agent is directly dispensed as 0.5 to 1 ml aliquots insmall vials.

If the alpha hydroxyacid, or the alpha ketoacid or the related compoundat full strength is a solid form at room temperature such as2-hydroxyethanoic acid, 2-methyl 2-hydroxypropanoic acid, 2-phenyl2-hydroxyethanoic acid, 2,2-diphenyl 2-hydroxyethanoic acid and 2-phenyl3-hydroxypropanoic acid, the solid compound is first dissolved in aminimal amount of vehicle or vehicle system such as water, or ethanoland propylene glycol with or without a gelling agent. For example,2-hydroxyethanoic acid 70 g is dissolved in water 30 g, and the 70%strength solution thus obtained is dispensed as 0.5 to 1 ml aliquots insmall vials. If a gelling agent is used, 0.5 to 3% of for example,hydroxyethyl cellulose, methyl cellulose, hydroxypropyl cellulose orcarbomer may be incorporated into the above solution.

To prepare an intermediate strength (usually 20-50%), the alphahydroxyacid, alpha ketoacid or related compound either a liquid or solidform at room temperature is first dissolved in a vehicle or vehiclesystem such as water, acetone, ethanol, propylene glycol and butane1,3-diol. For example, 2-hydroxyethanoic acid or 2-ketopropanoic acid 30g is dissolved in ethanol 56 g and propylene glycol 14 g, and the 30%strength solution thus obtained is dispensed as 7 to 14 ml aliquots indropper bottles.

For topical treatment of warts, keratoses, age spots, acne, nailinfections, wrinkles or aging related skin changes, patients are advisedto apply a small drop of the medication with a toothpick or afine-caliber, commonly available artist's camel hair brush to affectedlesions only and not surrounding skin. Prescribed applications have been1 to 6 times daily for keratoses and ordinary warts of the hands,fingers, palms, and soles. For age spots, acne, nail infections,wrinkles and aging related skin changes topical applications have been 1to 2 times daily.

Very often, frequency and duration of applications have been modifiedaccording to clinical responses and reactions of the lesions and thepatient or responsible family member is instructed accordingly. Forexample, some clinical manifestations other than pain have been used asa signal to interrupt application. These manifestations include distinctblanching of the lesions or distinct peripheral erythema.

Alternatively, an office procedure may be adapted when a full strengthof 2-ketopropanoic acid or 70% 2-hydroxyethanoic acid is used fortopical treatment of age spots, keratoses, acne, warts or facialwrinkles.

We have found that the above mentioned alpha hydroxyacids, alphaketoacids and related compounds are therapeutically effective fortopical treatments of warts, keratoses, age spots, acne, nailinfections, wrinkles and aging related skin changes.

Preparation of the Therapeutic Compositions

Amphoteric and pseudoamphoteric compositions of the instant inventionmay be formulated as solution, gel, lotion, cream, ointment, shampoo,spray, stick, powder or other cosmetic and pharmaceutical preparations.

To prepare an amphoteric or pseudoamphoteric composition in solutionform at least one of the aforementioned amphoteric or pseudoamphotericcompounds and in combination at least one of the hydroxyacids or therelated compounds are dissolved in a solution which may consist ofethanol, water, propylene glycol, acetone or other pharmaceuticallyacceptable vehicle. The concentration of the amphoteric orpseudoamphoteric compound may range from 0.01 to 10M, the preferredconcentration ranges from 0.1 to 3M. The concentration of hydroxyacidsor the related compounds may range from 0.02 to 12M, the preferredconcentration ranges from 0.2 to 5M.

In the preparation of an amphoteric or pseudoamphoteric composition inlotion, cream or ointment form, at least one of the amphoteric orpseudoamphoteric compounds and one of the hydroxyacids or the relatedcompounds are initially dissolved in a solvent such as water, ethanoland/or propylene glycol. The solution thus prepared is then mixed in aconventional manner with commonly available cream or ointment base suchas hydrophilic ointment or petrolatum. The concentrations of amphotericor pseudoamphoteric compounds and hydroxyacids used in the compositionsare the same as described above.

Amphoteric and pseudoamphoteric compositions of the instant inventionmay also be formulated in a gel form. A typical gel composition of theinstant invention utilizes at least one of the amphoteric orpseudoamphoteric compounds and one of the hydroxyacids or the relatedcompounds are dissolved in a mixture of ethanol, water and propyleneglycol in a volume ratio of 40:40:20, respectively. A gelling agent suchas methyl cellulose, ethyl cellulose, hydroxyethylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose, carbomer orammoniated glycyrrhizinate is then added to the mixture with agitation.The preferred concentration of the gelling agent may range from 0.1 to 4percent by weight of the total composition.

Since dimeric and polymeric forms of hydroxyacids are less stable in thepresence of water or the like vehicle, cosmetic and pharmaceuticalcompositions should be prepared as anhydrous formulations. Typicalvehicles suitable for such formulations include mineral oil, petrolatum,isopropyl myristate, isopropyl palmitate, diisopropyl adipate, occtylpalmitate, acetone, squalene, squalane, silicone oils, vegetable oilsand the like. Therapeutic compositions containing dimeric or polymericforms of hydroxyacids do not require any incorporation of an amphotericor pseudoamphoteric compound. The concentration of the dimeric orpolymeric form of a hydroxyacid used in the composition may range from0.1 to 100%, the preferred concentration ranges from 1 to 40%.Therapeutic compositions may be formulated as anhydrous solution,lotion, ointment, spray, powder or the like.

To prepare a combination composition in a pharmaceutically acceptablevehicle, a cosmetic or pharmaceutical agent is incorporated into any oneof the above composition by dissolving or mixing the agent into theformulation.

The following are illustrative examples of formulations and compositionsaccording to this invention. Although the examples utilize only selectedcompounds and formulations, it should be understood that the followingexamples are illustrative and not limited. therefore, any of theaforementioned amphoteric or pseudoamphoteric compounds, hydroxyacids,dimeric or polymeric forms of hydroxyacids may be substituted accordingto the teachings of this invention in the following examples.

EXAMPLE 1

An amphoteric composition containing 1M 2-hydroxyethanoic acid and 0.5ML-arginine in solution form for dandruff or dry skin may be formulatedas follows.

2-Hydroxyethanoic acid (glycolic acid) 7.6 g is dissolved in water 60 mland propylene glycol 20 ml. L-Arginine 8.7 g is added to the solutionwith stirring until all the crystals are dissolved. Ethanol is added tomake a total volume of the solution to 100 ml. The amphotericcomposition thus formulated has pH 3.0. An amphoteric compositionformulated from 1M 2-hydroxyethanoic acid and 1M L-arginine has pH 6.3.The solution has pH 1.9 if no amphoteric compound is incorporated.

EXAMPLE 2

An amphoteric composition containing 1M 2-hydroxyethanoic acid and 0.5ML-lysine in a cream form for dry skin and other dermatologic andcosmetic conditions may be formulated as follows.

2-Hydroxyethanoic acid 7.6 g and L-lysine 7.3 g are dissolved in 30 mlof water, and the solution thus obtained is mixed with sufficient amountof an oil-in-water emulsion to make a total volume Of 100 ml. Theamphoteric composition thus formulated has pH 3.3.

EXAMPLE 3

An amphoteric composition containing. 1M 2-hydroxyethanoic acid and 0.5M4-aminobutanoic acid in lotion form for cosmetic and dermatologicconditions may be formulated as follows.

2-Hydroxyethanoic acid 7.6 g and 4-aminobutanoic acid 5.2 g aredissolved in water 30 ml, and the solution is mixed with 50 g of anoil-in-water emulsion. The lotion thus obtained is made up to 100 ml involume with more oil-in-water emulsion. The amphoteric composition thusformulated has pH 3.1.

EXAMPLE 4

A pseudoamphoteric composition containing 1M 2-hydroxyethanoic acid and0.5M creatinine in solution form for cosmetic conditions anddermatologic disorders may be formulated as follows.

2-Hydroxyethanoic acid 7.6 g is dissolved in water 70 ml and propyleneglycol 10 ml. Creatinine 5.7 g is added to the solution with stirringuntil all the crystals are dissolved. More water is added to make atotal volume of the solution to 100 ml. The pseudoamphoteric compositionthus formulated has pH 3.2. The composition has pH 4.0 when 1M insteadof 0.5M creatinine is incorporated into the formulation.

EXAMPLE 5

An amphoteric composition containing 1M 2-hydroxyethanoic acid and 0.5ML-histidine in a cream form for dermatologic and cosmetic conditions maybe formulated as follows.

2-Hydroxyethanoic acid 7.6 g and L-histidine 7.8 g are dissolved in 25ml of water, and the solution thus obtained is mixed with sufficientamount of an oil-in-water emulsion to make a total volume of 100 ml. Theamphoteric composition thus formulated has pH 3.2.

EXAMPLE 6

An amphoteric composition containing 0.5M 2-hydroxyethanoic acid and0.5M dipeptide of β-Ala-L-His for cosmetic and dermatologic conditionsmay be formulated as follows.

2-Hydroxyethanoic acid 3.8 g and L-carnosine (β-alanyl-L-histidine) 11.3g are dissolved in water 40 ml and propylene glycol 20 ml. After all thecrystals have been dissolved sufficient amount of ethanol is added tomake a total volume of the solution to 100 ml. The amphotericcomposition thus formulated has pH 4.5.

EXAMPLE 7

An amphoteric composition containing 0.5M 2-hydroxyethanoic acid and0.5M cycloleucine for cosmetic and dermatologic conditions may beformulated as follows.

2-Hydroxyethanoic acid 3.8 g and 1-aminocyclopentane-1-carboxylic acid(cycloleucine) 6.5 g are dissolved in water 40 ml and propylene glycol20 ml. After all the crystals have been dissolved sufficient amount ofethanol is added to make a total volume of the solution to 100 ml. Theamphoteric composition thus formulated has pH 3.2.

EXAMPLE 8

A pseudoamphoteric composition containing 0.5M 2-hydroxyethanoic acidand 0.25M 1,12-diaminododecane for cosmetic and dermatologic conditionsmay be formulated as follows.

2-Hydroxyethanoic acid 3.8 g and 1.12-diaminododecane 5 g are dissolvedin water 40 ml and propylene glycol 20 ml. After all the crystals havebeen dissolved sufficient amount of ethanol is added to make a totalvolume of the solution to 100 ml. The pseudoamphoteric composition thusformulated has pH 4.2.

EXAMPLE 9

An amphoteric composition containing 0.5M 2-hydroxyethanoic acid and 5%protamine for cosmetic and dermatologic conditions may be formulated asfollows.

2-Hydroxyethanoic acid 3.8 g and protamine 5 g, isolated and purifiedfrom salmon sperm are dissolved in water 25 ml. The solution thusobtained is mixed with sufficient amount of an oil-in-water emulsion tomake a total volume of 100 ml. The amphoteric composition thusformulated has pH 3.2.

EXAMPLE 10

An amphoteric composition containing 1M 2-hydroxypropanoic acid and 0.5ML-arginine in solution form for dandruff or dry skin may be formulatedas follows.

2-Hydroxypropanoic acid (DL-lactic acid) USP grade 9.0 g is dissolved inwater 60 ml and propylene glycol 20 ml. L-Arginine 8.7 g is added to thesolution with stirring until all the crystals are dissolved. Ethanol isadded to make a total volume of the solution to 100 ml. The amphotericcomposition thus formulated has pH 3.1. An amphoteric compositionformulated from 1M 2-hydroxypropanoic acid and 1M L-arginine has pH 6.9.The solution has pH 1.9 if no amphoteric compound is incorporated.

EXAMPLE 11

An amphoteric composition containing 1M 2-hydroxypropanoic acid and 0.5ML-lysine in a cream form for dry skin and other dermatologic andcosmetic conditions may be formulated as follows.

2-Hydroxypropanoic acid 9.0 g and L-lysine 7.3 g are dissolved in 30 mlof water, and the solution thus obtained is mixed with sufficient amountof an oil-in-water emulsion to make a total volume of 100 ml. Theamphoteric composition thus formulated has pH 3.6. An amphotericcomposition formulated from 1M 2-hydroxypropanoic acid and 1M L-lysinehas pH 8.4

EXAMPLE 12

An amphoteric composition containing 1M 2-hydroxypropanoic acid and 0.5M4-aminobutanoic acid in lotion form for cosmetic and dermatologicconditions may be formulated as follows.

2-Hydroxypropanoic acid 9.0 g and 4-aminobutanoic acid 5.2 g aredissolved in water 30 ml, and the solution is mixed with 50 g of anoil-in-water emulsion. The lotion thus obtained is made up to 100 ml involume with more oil-in-water emulsion. The amphoteric composition thusformulated has pH 3.0

EXAMPLE 13

A pseudoamphoteric composition containing 1M 2-hydroxypropanoic acid and0.5M creatinine in solution form for cosmetic conditions anddermatologic disorders may be formulated as follows.

2-Hydroxypropanoic acid 9.0 g is dissolved in water 70 ml and propyleneglycol 10 ml. Creatinine 5.7 g is added to the solution with stirringuntil all the crystals are dissolved. More water is added to make atotal volume of the solution to 100 ml. The pseudoamphoteric compositionthus formulated has pH 3.3. The composition has pH 4.4 when 1M insteadof 0.5M creatinine is incorporated into the formulation.

EXAMPLE 14

An amphoteric composition containing 1M 2-hydroxypropanoic acid and 1ML-histidine in a cream form for dermatologic and cosmetic conditions maybe formulated as follows.

2-Hydroxypropanoic acid 9.0 g and L-histidine 15.5 g are dissolved in 35ml of water, and the solution thus obtained is mixed with sufficientamount of an oil-in-water emulsion to make a total volume of 100 ml. Theamphoteric composition thus formulated as pH 4.9.

EXAMPLE 15

An amphoteric composition containing 1M 2-hydroxypropanoic acid and 1Mdipeptide of Gly--Gly for cosmetic and dermatologic conditions may beformulated as follows.

2-Hydroxypropanoic acid 9.0 g and glycylglycine 13.2 g are dissolved inwater 40 ml and propylene glycol 20 ml. After all the crystals have beendissolved sufficient amount of ethanol is added to make a total volumeof the solution to 100 ml. The amphoteric composition thus formulatedhas pH 3.0.

EXAMPLE 16

An amphoteric composition containing 1M 2-methyl-2-hydroxypropanoic acidand 0.5M L-arginine in solution form for dandruff or dry skin may beformulated as follows.

2-Methyl-2-hydroxypropanoic acid (methyllactic acid) 10.4 g is dissolvedin water 60 ml and propylene glycol 20 ml. L-Arginine 8.7 g is added tothe solution with stirring until all the crystals are dissolved. Ethanolis added to make a total volume of the solution to 100 ml. Theamphoteric composition thus formulated has pH 3.3. An amphotericcomposition formulated from 1M 2-methyl-2-hydroxypropanoic acid and 1ML-arginine has pH 6.5. The solution has pH 1.9 if no amphoteric compoundis incorporated.

EXAMPLE 17

An amphoteric composition containing 1M 2-methyl-2-hydroxypropanoic acidand 0.5M 4-aminobutanoic acid in a cream form for dry skin and otherdermatologic and cosmetic conditions may be formulated as follows.

2-Methyl-2-hydroxypropanoic acid 10.4 g and 4-aminobutanoic acid 5.2 gare dissolved in 30 ml of water, and the solution thus obtained is mixedwith sufficient amount of an oil-in-water emulsion to make a totalvolume of 100 ml. The amphoteric composition thus formulated has pH 3.2.

EXAMPLE 18

An amphoteric composition containing 1M 2-methyl-2-hydroxypropanoic acidand 1M dipeptide of Gly--Gly in lotion form for cosmetic anddermatologic conditions may be formulated as follows.

2-Methyl-2-hydroxypropanoic acid 10.4 g and glycylglycine 13.2 g aredissolved in water 30 ml, and the solution is mixed with 50 g of anoil-in-water emulsion. The lotion thus obtained is made up to 100 ml involume with more oil-in-water emulsion. The amphoteric composition thusformulated has pH 3.0.

EXAMPLE 19

A pseudoamphoteric composition containing 1M 2-methyl-2-hydroxypropanoicacid and 0.5M creatinine in solution form for cosmetic conditions anddermatologic disorders may be formulated as follows.

2-Methyl-2-hydroxypropanoic acid 10.4 g is dissolved in water 70 ml andpropylene glycol 10 ml. Creatinine 5.7 g is added to the solution withstirring until all the crystals are dissolved. More water is added tomake a total volume of the solution to 100 ml. The pseudoamphotericcomposition thus formulated has pH 3.4. The composition has pH 4.4 when1M instead of 0.5M creatinine is incorporated into the formulation.

EXAMPLE 20

An amphoteric composition containing 0.5M 2-phenyl-2-hydroxyethanoicacid and 0.5M L-histidine in a cream form for dermatologic and cosmeticconditions may be formulated as follows.

2-Phenyl 2-hydroxyethanoic acid (mandelic acid) 7.6 g and L-histidine7.8 g are dissolved in 25ml of water, and the solution thus obtained ismixed with sufficient amount of an oil-in-water emulsion to make a totalvolume of 100 ml. The amphoteric composition thus formulated has pH 5.0.The composition has pH 2.2 if no amphoteric compound is incorporated.

EXAMPLE 21

An amphoteric composition containing 0.5M 2-phenyl-2-hydroxyethanoicacid and 0.5M L-lysine for cosmetic and dermatologic conditions may beformulated as follows.

2-Phenyl 2-hydroxyethanoic acid 7.6 g and L-lysine 7.3 g are dissolvedin 25 ml of water. The solution thus obtained is mixed with anoil-in-water emulsion to make a total volume of 100 ml. The amphotericcomposition thus formulated for pH 4.6.

EXAMPLE 22

A pseudoamphoteric composition containing 0.5M 2-phenyl2-hydroxyethanoic acid and 0.5M creatinine for cosmetic and dermatologicconditions may be formulated as follows.

2-Phenyl 2-hydroxyethanoic acid 7.6 g and creatinine 5.7 g are dissolvedin 30 ml of water, and the solution thus obtained is mixed withsufficient amount of an oil-in-water emulsion to make a total volume of100 ml. The amphoteric composition thus formulated has pH 4.6.

EXAMPLE 23

An amphoteric composition containing 0.5M 2-phenyl 2-hydroxyethanoicacid and 0.5M L-citrulline for cosmetic and dermatologic conditions maybe formulated as follows.

2-Phenyl 2-hydroxyethanoic acid 7.6 g and L-citrulline 8.8 g aredissolved in water 30 ml, and the solution is mixed with 50 g of anoil-in-water emulsion. The lotion thus obtained is made up to 100 ml involume with more oil-in-water emulsion. The amphoteric composition thusformulated has pH 3.0.

EXAMPLE 24

An amphoteric composition containing 1M citric acid and 1M L-argininefor cosmetic conditions and dermatologic disorders may be formulated asfollows. Citric acid 19.2 g is dissolved in water 50 ml and propyleneglycol 10 ml. L-Arginine 17.4 g is added to the solution with stirringuntil all the crystals are dissolved. More water is added to make atotal volume of the solution to 100 ml. The amphoteric composition thusformulated has pH 3.0. The composition has pH 1.8 if no amphotericcompound is incorporated.

EXAMPLE 25

A pseudoamphoteric composition containing 1M citric acid and 1Mcreatinine for dermatologic and cosmetic conditions may be formulated asfollows.

Citric acid 19.2 g and creatinine 11.3 g are dissolved in 40 ml ofwater, and the solution thus obtained is mixed with sufficient amount ofan oil-in-water emulsion to make a total volume of 100 ml. Theamphoteric composition thus formulated has pH 3.7.

EXAMPLE 26

An amphoteric composition containing 1M malic acid and 1M L-arginine forcosmetic and dermatologic conditions may be formulated as follows.

2-Hydroxybutanedioic acid (DL-malic acid) 13.4 g and L-arginine 17.4 gare dissolved in water 40 ml and propylene glycol 20 ml. After all thecrystals have been dissolved sufficient amount of water is added to makea total volume of the solution to 100 ml. The amphoteric compositionthus formulated has pH 3.3. The composition has pH 1.8 if no amphotericcompound is incorporated.

EXAMPLE 27

A pseudoamphoteric composition containing 1M malic acid and 0.5Mcreatinine for cosmetic and dermatologic conditions may be formulated asfollows.

DL-Malic acid 13.4 g and creatinine 5.7 g are dissolved in water 40 mland propylene glycol 20 ml. After all the crystals have been dissolvedsufficient amount of water is added to make a total volume of thesolution to 100 ml. The pseudoamphoteric composition thus formulated haspH 3.0. The composition has pH 3.8 when 1M instead of 0.5M creatinine isincorporated into the formulation.

EXAMPLE 28

An amphoteric composition containing 1M tartaric acid and 1M L-argininefor cosmetic and dermatologic conditions may be formulated as follows.

2,3-Dihydroxybutanedioic acid (DL-tartaric acid) 15.9 g and L-arginine17.4 g are dissolved in water 40 ml and propylene glycol 20 ml. Afterall the crystals have been dissolved sufficient amount of water is addedto make a total volume of the solution to 100 ml. The amphotericcomposition thus formulated has pH 3.0. The composition has pH 1.7 if noamphoteric compound is incorporated.

EXAMPLE 29

A pseudoamphoteric composition containing 1M tartaric acid and 1Mcreatinine for cosmetic and dermatologic conditions may be formulated asfollows.

DL-Tartaric acid 15.0 g and creatinine 11.3 g are dissolved in 35 ml ofwater. The solution thus obtained is mixed with sufficient amount of anoil-in-water emulsion to make a total volume of 100 ml. Thepseudoamphoteric composition thus formulated has pH 3.4.

EXAMPLE 30

An amphoteric composition containing 1M gluconolactone and 0.5ML-arginine for cosmetic and dermatologic conditions may be formulated asfollows.

Gluconolactone 17.8 g and L-arginine 8.7 g are dissolved in water 60 mland propylene glycol 10 ml. After all the crystals have been dissolvedsufficient water is added to make a total volume of the solution to 100ml. The amphoteric composition thus formulated has pH 3.1. Thecomposition has pH 5.9 when 1M instead of 0.5M L-arginine isincorporated into the formulation. If no amphoteric compound isincorporated the pH of the composition is 1.8.

EXAMPLE 31

An amphoteric composition containing 1M gluconolactone and 0.5M4-aminobutanoic acid for cosmetic and dermatologic conditions may beformulated as follows.

Gluconolactone 17.8 g and 4-aminobutanoic acid 5.2 g are dissolved inwater 60 ml and propylene glycol 10 ml. After all the crystals ave beendissolved sufficient water is added to make a total volume of thesolution to 100 ml. The amphoteric composition thus formulated has pH3.2.

EXAMPLE 32

An amphoteric composition containing 1M gluconolactone and 1M dipeptideof Gly--Gly for cosmetic and dermatologic conditions may be formulatedas follows.

Gluconolactone 17.8 g and glycylglycine 13.2 g are dissolved in water 50ml and propylene glycol 5 ml. More water is added to make a total volumeof the solution to 100 mi. The amphoteric composition thus formulatedhas pH 3.1

EXAMPLE 33

A pseudoamphoteric composition containing 1M gluconolactone and 0.5Mcreatinine for cosmetic conditions and dermatologic disorders may beformulated as follows.

Gluconolactone 17.8 g and creatinine 5.7 g are dissolved in water 60 mland propylene glycol 10 ml. More water is added to make a total volumeof the solution to 100 ml. The pseudoamphoteric composition thusformulated has pH 3.2. The composition has pH 4.8 when 1M instead of0.5M creatinine is incorporated into the formulation.

EXAMPLE 34

A pseudoamphoteric composition containing 1M pyruvic acid and 1Mcreatinine for dermatologic and cosmetic conditions may be formulated asfollows.

2-Ketopropanoic acid (pyruvic acid) 8.8 g and creatinine 11.3 g aredissolved in water 25 ml. The solution thus obtained is mixed withsufficient amount of an oil-in-water emulsion to make a total volume of100 ml. The amphoteric composition thus formulated has pH 3.4.

EXAMPLE 35

An amphoteric composition containing 0.5M benzilic acid and 0.5ML-lysine for cosmetic and dermatologic conditions may be formulated asfollows.

2,2-Diphenyl 2-hydroxyethanoic acid (benzilic acid) 11.4 g and L-lysine7.3 g are dissolved in water 40 ml and propylene glycol 20 ml. After allthe crystals have been dissolved sufficient amount of ethanol is addedto make a total volume of the solution to 100 ml. The amphotericcomposition thus formulated has pH 4.9. The composition has pH 2.7 if noamphoteric compound is incorporated.

EXAMPLE 36

An amphoteric composition containing 0.5M benzilic acid and 0.5ML-histidine for cosmetic and dermatologic conditions may be formulatedas follows.

Benzilic acid 11.4 g and L-histidine 7.8 g are dissolved in water 40 mland propylene glycol 20 ml. Ethyl cellulose 2 g is added with stirring,and sufficient amount of ethanol is added to make a total volume of thegel to 100 ml. The amphoteric gel composition thus formulated has pH5.0.

EXAMPLE 37

A pseudoamphoteric composition containing 0.5M benzilic acid and 0.5Mcreatinine for cosmetic and dermatologic conditions may be formulated asfollows.

Benzilic acid 11.4 g and creatinine 5.7 g are dissolved in water 40 mland propylene glycol 20 ml. Sufficient amount of ethanol is added tomake a total volume of the solution to 100 ml. The amphotericcomposition thus formulated has pH 4.9.

EXAMPLE 38

A pseudoamphoteric composition containing in combination 0.5M2-hydroxyethanoic acid and 0.05% betamethasone dipropionate in a creamform for dermatologic disorders may be formulated as follows.

2-Hydroxyethanoic acid 3.8 g and creatinine 5.7 g are dissolved in 25 mlof water, and the solution thus obtained is mixed with 50 g of anoil-in-water emulsion. Betamethasone dipropionate 1% in ethanol solution5 ml is added to the above mixture. More oil-in-water emulsion is addedto make a total volume of 100 ml. The pseudoamphoteric composition thusformulated has pH 4.2.

EXAMPLE 39

A pseudoamphoteric composition containing in combination 0.5M2-hydroxyethanoic acid and 0.05% clobetasol propionate in a cream formfor dermatologic disorders may be formulated as follows.

2-Hydroxyethanoic acid 3.8 g and creatinine 5.7 g are dissolved in 25 mlof water, and the solution thus obtained is mixed with 50 g of anoil-in-water emulsion. Clobetasol propionate 1% in acetone solution 5 mlis added to the above mixture. More oil-in-water emulsion is added tomake a total volume of 100 ml. The pseudoamphoteric composition thusformulated has pH 4.2.

EXAMPLE 40

A pseudoamphoteric composition containing in combination 0.5M2-hydroxyethanoic acid and 0.1% triamcinolone acetonide in a cream formfor dermatologic disorders may be formulated as follows.

2-Hydroxyethanoic acid 3.8 g and creatinine 5.7 g are dissolved in 25 mlof water, and the solution thus obtained is mixed with 50 g of anoil-in-water emulsion. Triamcinolone acetonide 2% solution ofacetone:ethanol (50:50), 5 ml is added to the above mixture. Moreoil-in-water emulsion is added to make a total volume of 100 ml. Thepseudo amphoteric composition thus formulated has pH 4.2.

EXAMPLE 41

A pseudoamphoteric composition containing in combination 0.5M2-hydroxyethanoic acid and 0.2% 5-fluorouracil in a cream form fordermatologic disorders may be formulated as follows.

2-Hydroxyethanoic acid 3.8 g and creatinine 5.7 g are dissolved in 20 mlof water, and the solution thus obtained is mixed with 50 g of anoil-in-water emulsion. 5-Fluorouracil 2% solution of propylene glycol:water (95:5), 10 ml is added to the above mixture. More oil-in-wateremulsion is added to make a total volume of 100 ml. The pseudoamphotericcomposition thus formulated has pH 4.1.

EXAMPLE 42

A pseudoamphoteric composition containing in combination 0.5M2-hydroxypropanoic acid and 0.05% betamethasone dipropionate in a creamform for dermatologic disorders may be formulated as follows.2-Hydroxypropanoic acid 4.5 g and creatinine 5.7 g are dissolved in 25ml of water, and the solution thus obtained is mixed with 50 g of aoil-in-water emulsion. Betamethasone dipropionate 1% in ethanol solution5 ml is added to the above mixture. More oil-in-water emulsion is addedto make a total volume of 100 ml. The pseudoamphoteric composition thusformulated has pH 4.1.

EXAMPLE 43

A pseudoamphoteric composition containing in combination 0.5Mhydroxypropanoic acid and 0.05% clobetasol propionate in a cream formfor dermatologic disorders may be formulated as follows.

2-Hydroxypropanoic acid 4.5 g and creatinine 5.7 g are dissolved in 25ml of water, and the solution thus obtained is mixed with 50 g of anoil-in-water emulsion. Clobetasol propionate 1% in acetone solution 5 mlis added to the above mixture. More oil-in-water emulsion is added tomake a total volume of 100 ml. The pseudoamphoteric composition thusformulated has pH 4.1.

EXAMPLE 44

A pseudoamphoteric composition containing in combination 0.5M2-hydroxypropanoic acid and 0.1% triamcinolone acetonide in a cream formfor dermatologic disorders may be formulated as follows.

2-Hydroxypropanoic acid 4.5 g and creatinine 5.7 g are dissolved in 25ml of water, and the solution thus obtained is mixed with 50 g of anoil-in-water emulsion. Triamcinolone acetonide 2% solution ofacetone:ethanol (50:50), 5 ml is added to the above mixture. Moreoil-in-water emulsion is added to make a total volume of 100 ml. Thepseudoamphoteric composition thus formulated has pH 4.1.

EXAMPLE 45

A pseudoamphoteric composition containing in combination 0.5M2-hydroxypropanoic acid and 0.2% 5-fluorouracil in a cream form fordermatologic disorders may be formulated as follows.

2-Hydroxypropanoic acid 4.5 g and creatinine 5.7 g are dissolved in 20ml of water, and the solution thus obtained is mixed with 50 g of anoil-in-water emulsion. 5-Fluorouracil 2% solution of propyleneglycol:water (95:5), 10 ml is added to the above mixture. Moreoil-in-water emulsion is added to make a total volume of 100 ml. Thepseudoamphoteric composition thus formulated has pH 4.1.

EXAMPLE 46

A pseudoamphoteric composition containing in combination 0.5M2-hydroxyethanoic acid and 2% clotrimazole in a cream form for athlete'sfoot and other fungal infections may be formulated as follows.

2-Hydroxyethanoic acid 3.8 g, clotimazole 2 g and creatinine 5.7 g aredissolved in water 20 ml and propylene glycol 5 ml, and the solutionthus obtained is mixed with enough amount of an oil-in-water emulsion tomake a total volume of 100 ml. The pseudoamphoteric composition thusformulated has pH 4.2.

EXAMPLE 47

A pseudoamphoteric composition containing in combination 0.5M2-hydroxyethanoic acid and 2% erythromycin in solution form for acne maybe formulated as follows.

2-Hydroxyethanoic acid 3.8 g, erythromycin 2 g and creatinine 5.7 g aredissolved in water 25 ml, ethanol 40 ml and propylene glycol 15 ml. Morewater is then added to make a total volume of 100 ml. Thepseudoamphoteric composition thus formulated has pH 4.2.

EXAMPLE 48

A pseudoamphoteric composition containing in combination 0.5M2-hydroxyethanoic acid and 1% ketoconazole in a cream form for fungalinfections may be formulated as follows.

2-Hydroxyethanoic acid 3.8 g, ketoconazole 1 g and creatinine 5.7 g aredissolved in 25 ml of water, and the solution thus obtained is mixedwith enough amount of an oil-in-water emulsion to make a total volume of100 ml. The pseudoamphoteric composition thus formulated has pH 4.2.

EXAMPLE 49

A pseudoamphoteric composition containing in combination 0.5M2-hydroxypropanoic acid and 2% clotrimazole in a cream form for fungalinfections may be formulated as follows.

2-Hydroxypropanoic acid 3.8 g, clotrimazole 2 g and creatinine 5.7 g aredissolved in 25 ml of water, and the solution thus obtained is mixedwith enough amount of an oil-in-water emulsion to make a total volume of100 ml. The pseudoamphoteric composition thus formulated has pH 4.1.

EXAMPLE 50

A pseudoamphoteric composition containing in combination 0.5M2-hydroxyethanoic acid and 2% tetracycline in a gel form fordermatologic disorders may be formulated as follows.

2-Hydroxyethanoic acid 3.8 g, tetracycline 2 creatinine 5.7 g, xanthamgum 0.2 g, carbomer-941 1 g, propylene glycol 5 ml, ethanol 20 ml andenough amount of water are homogenized to make a total volume of 100 ml.The pseudoamphoteric composition thus formulated for acne and oily skinhas pH 4.2.

EXAMPLE 51

An amphoteric composition containing 0.2M aleuritic acid and 0.1ML-lysine in a solution form for cosmetic and dermatologic conditions maybe formulated as follows.

Aleuritic acid 6.1 g and L-lysine 1.5 g are dissolved in sufficientamount of a solution from ethanol:propylene glycol 80:20 to make a totalvolume of 100 ml. The amphoteric composition thus formulated has pH 6.4.

EXAMPLE 52

A typical composition containing a dimeric form of alpha hydroxyacid insolution for acne, dandruff, and as a skin cleanser may be formulated asfollows.

Glycolide powder 1.0 g is dissolved in ethanol 89 ml and propyleneglycol 10 ml. The composition thus formulated has pH 4.0, and contains1% active ingredient.

EXAMPLE 53

A typical composition containing a dimeric form of alpha hdyroxyacid inointment for dry skin, psoriasis, eczema, pruritus, wrinkles and otherskin changes associated with aging may be formulated as follows.

Glycolide powder 2.0 g is mixed uniformly with petrolatum 66 g andmineral oil 32 g. The composition thus formulated contains 2% activeingredient.

EXAMPLE 54

A typical composition containing a full strength or a high concentrationof an alpha hydroxyacid, alpha ketoacid or closely related compound fortopical treatments of warts, keratoses, acne, age spots, nailinfections, wrinkles and aging related skin changes may be prepared asfollows.

If the alpha hydroxyacid, alpha ketoacid or closely related compound atfull strength is a liquid form at room temperature such as2-hydroxypropanoic acid, 2-ketopropanoic acid, methyl 2-ketopropanoateand ethyl 2-ketopropanoate, the compound is directly dispensed as 0.5 to1 ml aliquots in small vials. If the compound is a solid form at roomtemperature such as 2-hydroxyethanoic acid and 2-methyl2-hydroxypropanoic acid, it is first dissolved in minimal amount of anappropriate solvent or solvent system such as water or ethanol andpropylene glycol with or without a gelling agent. For example,2-hydroxyethanoic acid 70 g is dissolved in water 30 ml, and the 70%strength 2-hydroxyethanoic acid thus obtained is dispensed as 0.5 to 1ml aliquots in small vials. If a gelling agent is used, methyl celluloseor hydroxyethyl cellulose 1 g may be added to the above solution.

EXAMPLE 55

A typical composition containing an intermediate strength of an alphahydroxyacid, alpha ketoacid or closely related compound for topicaltreatment of warts, keratoses, acne, nail infections, age spots,wrinkles and aging related skin changes may be prepared as follows.

2-Hydroxyethanoic acid or 2-ketopropanoic acid 40 g is dissovled inethanol 54 g and propylene glycol 6 g, and the 40% strength solutionthus obtained is dispensed as 5 to 10 ml aliquots in dropper bottles.

TEST RESULTS

In order to determine whether amphoteric and pseudoamphotericcompositions of the instant invention were therapeutically effective forvarious cosmetic conditions and dermatologic disorders, a total of morethan 90 volunteers and patients participated in these studies. Someparticipating subjects were given two preparations; an amphoteric orpseudoamphoteric composition containing an alpha hydroxyacid or therelated compound, and a vehicle placebo. Others were given multiplepreparations containing a known pharmaceutical agent such as acorticosteroid with or without incorporation of an amphoteric orpseudoamphoteric composition consisting of an alpha hydroxyacid or therelated compound of the instant invention. The amphoteric andpseudoamphoteric compositions were formulated according to the Examplesdescribed in the previous section.

1. Common dry skin.

Human subjects having ordinary dry skin or with moderate degrees of dryskin as evidenced by dryness, flaking and cracking of the skin wereinstructed to apply topically the lotion, cream or ointment containingan alpha hydroxyacid or the related compound in amphoteric orpseudoamphoteric composition, on the affected area of the skin. Topicalapplication, two to three times daily, was continued for two to fourweeks.

In all the 28 subjects tested, the feeling of the skin drynessdisappeared within a week of topical application. The rough and crackedskin became less pronounced and the skin appeared normal and felt smoothafter several days of topical treatment. The alpha hydroxyacids and therelated compounds which have been found to be therapeutically effectivewhen incorporated into the amphoteric or pseudoamphoteric compositionsfor dry skin are as follows:

2-hydroxyethanoic acid (glycolic acid), 2-hydroxypropanoic acid (lacticacid), 2-methyl-2-hydroxypropanoic acid (methyllactic acid), phenyl2-hydroxyethanoic acid (mandelic acid), phenyl2-methyl-2-hydroxyethanoic acid (atrolactic acid),3-phenyl-2-hydroxypropanoic acid (phenyllactic acid), diphenyl2-hydroxyethanoic acid (benzilic acid), gluconolactone, tartaric acid,citric acid, saccharic acid, malic acid, tropic acid, glucuronic acid,galacturonic acid, gluconic acid, 3-hydroxybutanoic acid, quinic acid,ribonolactone, glucuronolactone, galactonolactone, pyruvic acid, methylpyruvate, ethyl pyruvate, phenylpyruvic acid, benzoylformic acid andmethyl benzoylformate.

The ordinary dry skin conditions, once restored to normal appearingskin, remained improved for some time until causes of dry skin, such aslow humidity, cold weather, excessive contact pressure, detergents,soaps, solvents, chemicals, etc., again caused recurrence of the dryskin condition. On continued use it was also found that twice dailytopical application of an amphoteric or Pseudoamphoteric compositioncontaining an alpha hydroxyacid or the related compound of the instantinvention prevented the development of new dry skin lesions.

2. Severe dry skin.

In severe dry skin, the skin lesions are different from the ordinary dryskin. A main cause of severe dry skin is inherited genetic defects ofthe skin. The involved skin is hyperplastic, fissured and has thickadherent scales. The degree of thickening is such that lesions arepalpably and visually elevated. The thickened adherent scales cause thesurface of involved skin to be markedly rough and uneven. These twoattributes of thickness and texture can be quantified to allow objectivemeasurement of degree of improvement from topically applied testmaterials as follows:

    ______________________________________                                        DEGREE OF IMPROVEMENT                                                         None       Mild     Moderate  Substantial                                                                           Complete                                (0)        (1+)     (2+)      (3+)    (4+)                                    ______________________________________                                        Thickness                                                                            Highly  Detectable                                                                             Readily Barely  Normal                                       elevated                                                                              reduction                                                                              apparent                                                                              elevated                                                                              thickness                                                     reduction                                             Texture                                                                              Visibly Palpably Uneven but                                                                            Slightly                                                                              Visibly                                      rough   rough    not rough                                                                             uneven  and                                                                           palpably                                                                      smooth                                ______________________________________                                    

By means of such parameters, degrees of change in lesions can benumerically recorded and comparisons made of one treated site toanother.

In order to evaluate the amphoteric and pseudoamphoteric compositions ofthe instant invention, a total of 6 patients having severe dry skinconditions were treated with the compositions containing an alphahydroxyacid or the related compound.

Tested areas were of a size convenient for topical applications, i.e.,circles 5 cm in diameter demarcated with a plastic ring of that sizeinked on a stamp pad. The medicinal lotions or creams were topicallyapplied by the patient in an amount sufficient to cover the treatmentsites. Applications were made three times daily and without occlusivedressings. Applications were discontinued at any time when resolutionsof the lesion on the treatment area was clinically judged to becomplete.

The test results of amphoteric and pseudoamphoteric compositionscontaining the following alpha hydroxyacids or the related compounds onpatients with severe dry skin are summarized as follows:

4+ Effectiveness; glycolic acid, lactic acid, methyllactic acid,mandelic acid, tropic acid, atrolactic acid and pyruvic acid.

3+ Effectiveness; benzilic acid, gluconolactone, malic acid, tartaricacid, citric acid, saccharic acid, methyl pyruvate, ethyl pyruvate,phenyllactic acid, phenylpyruvic acid, glucuronic acid and3-hydroxybutanoic acid.

2+ Effectiveness; mucic acid, ribonolactone, hydroxydodecanoic acid,quinic acid, benzoylformic acid and methyl benzoylformate.

3. Psoriasis.

The involved skin in psoriasis is hyperplastic (thickened), erythematous(red or inflamed), and has thick adherent scales. The degree ofthickening is such that lesions are elevated up to 1 mm above thesurface of adjacent normal skin; erythema is usually an intense red; thethickened adherent scales cause the surface of involved skin to bemarkedly rough and uneven. These three attributes of thickness, colorand texture can be quantified to allow objective measurement of degreeof improvement from topically applied test materials as follows.

    ______________________________________                                        DEGREE OF IMPROVEMENT                                                         None        Mild    Moderate  Substantial                                                                           Complete                                (0)         (1+)    (2+)      (3+)    (4+)                                    ______________________________________                                        THICK-  Highly  Detect- Readily Barely  Normal                                NESS    elevated                                                                              able    apparent                                                                              elevated                                                                              thickness                                             reduct- reduction                                                             ion                                                           TEXTURE Visibly Palpa-  Uneven but                                                                            Slightly                                                                              Visibly                                       rough   bly     not rough                                                                             uneven  and                                                   rough                   palpably                                                                      smooth                                COLOR   Intense Red     Dark    Light   Normal                                        Red             Pink    Pink    Skin                                                                          Color                                 ______________________________________                                    

By means of such parameters, degree of improvement in psoriatic lesionscan be numerically recorded and comparisons made of one treated site toanother.

Patients having psoriasis participated in this study. Amphoteric andpseudoamphoteric compositions containing both an alpha hdyroxyacid orthe related compound and a corticosteroid were prepared according to theExamples. Compositions containing only a corticosteroid were alsoprepared and included in the comparison test. Test areas were kept tominimal size convenient for topical application, i.e., circlesapproximately 4 cm in diameter. The medicinal compositions weretopically applied by the patient in an amount (usually about 0.1milliliter) sufficient to cover the test site. Applications were madetwo to three times daily and without occlusive dressings. Test periodsusually lasted for two to four weeks. The test results on patientshaving psoriasis are summarized on the following table.

    ______________________________________                                        Topical Effects on Psoriasis of                                               Antipsoriatic Compositions                                                                       Therapeutic                                                Compositions*      Effectiveness                                              ______________________________________                                        Hydrocortisone 2.5% alone                                                                        1+                                                         With lactic acid   2+                                                         With glycolic acid 2+                                                         With ethyl pyruvate                                                                              2+                                                         With methyl pyruvate                                                                             2+                                                         With benzilic acid 2+                                                         With pyruvic acid  2+                                                         With methyllactic acid                                                                           2+                                                         Hydrocortisone 17- 2+                                                         valerate 0.2% alone                                                           With lactic acid   3+                                                         With glycolic acid 3+                                                         With benzilic acid 3+                                                         With ethyl pyruvate                                                                              3+                                                         With methyl pyruvate                                                                             3+                                                         With gluconolactone                                                                              3+                                                         With pyruvic acid  3+                                                         Betamethasone dipropionate                                                                       3+                                                         0.05% alone                                                                   With lactic acid   4+                                                         With glycolic acid 4+                                                         With ethyl pyruvate                                                                              4+                                                         With methyl pyruvate                                                                             4+                                                         With mandelic acid 4+                                                         With benzilic acid 4+                                                         Clobetasol propionate                                                                            3+                                                         0.05% alone                                                                   With lactic acid   4+                                                         With glycolic acid 4+                                                         With ethyl pyruvate                                                                              4+                                                         With methyl pyruvate                                                                             4+                                                         With methyllactic acid                                                                           4+                                                         With mandelic acid 4+                                                         With tropic acid   4+                                                         With benzilic acid 4+                                                         ______________________________________                                         *Except the "alone" preparations, all others were amphoteric or               pseudoamphoteric compositions containing 0.2 to 2M alpha hydroxyacids or      related compounds.                                                       

We have also found that an amphoteric or pseudoamphoteric compositioncontaining an alpha hydroxyacid or the related compound in combinationwith an antimetabolite agent such as 5-fluorouracil with or withoutadditional incorporation of a corticosteroid is therapeuticallyeffective for topical treatment of psoriasis.

4. Eczema.

In a topical treatment of eczema patients, hydrocortisone alone at 2.5%or hydrocortisone 17-valerate alone at 0.2% would achieve only 2+improvement, and betamethasone dipropionate or clobetasol propionatealone at 0.05% would achieve only a 3+ improvement on all the eczemapatients tested. Test results of amphoteric and pseudoamphotericcompositions containing both a corticosteroid and one of the followingalpha hydroxyacids or the related compounds are shown as follows:

3+ Effectiveness; hydrocortisone 2.5% or hydrocortisone 17-valerate 0.2%plus lactic acid, glycolic acid, mandelic acid, ethyl pyruvate,gluconolactone, benzilic acid or ribonolactone.

4+ Effectiveness; betamethasone dipropionate or clobetasol propionate0.05% plus lactic acid, glycolic acid, mandelic acid, ethyl pyruvate,methyl pyruvate, benzilic acid, gluconolactone, citric acid, tartaricacid or methyllactic acid.

5. Oily Skin and Skin Cleanse.

Human subjects having oily skin or blemished skin as well as achepatients having extremely oily skin participated in this study.Amphoteric and pseudoamphoteric compositions containing alphahydroxyacids or the related compounds were formulated in solution or gelform.

Each participating subject received a solution or a gel preparationcontaining an alpha hydroxyacid or a related compound in an amphotericor pseudoamphoteric composition. The participating subjects wereinstructed to apply topically the solution or gel medication on theaffected areas of forehead or other part of the face. Three times dailyapplications were continued for 2 to 6 weeks.

The degree of improvement of oily skin as well as the rate ofimprovement of acne lesions were clinically evaluated. Most participantsreported that oiliness of skin disappeared within one to two weeks oftopical administration, and the skin so treated became smooth and soft.Many participating subjects preferred gel preparations than solutioncompositions. It was found that all the participants showed substantialimprovements on oily skin and acne lesions by six weeks of topicaladministration of amphoteric or pseudoamphoteric compositions containingalpha hydroxyacids or the related compounds of the instant invention.

Those alpha hydroxyacids and the related compounds which have been foundto be therapeutically effective for oily skin and as skin cleansersinclude: benzilic acid, glycolic acid, lactic acid, methyllactic acid,mandelic acid, pyruvic acid, ethyl pyruvate, methyl pyruvate, tropicacid, malic acid, gluconolactone, 3-hydroxybutanoic acid, glycolide andpolyglycolic acid. As a skin cleanser for oily skin or acne-prone skin,the amphoteric or pseudoamphoteric composition containing an alphahydroxyacid or the related compound may also be incorporated with otherdermatologic agents. For example, an amphoteric gel composition mayconsist of both an alpha hydroxyacid and erythromycin or tetracycline.

6. Acne

Amphoteric and pseudoamphoteric compositions containing alphahydroxyacids or the related compounds of the instant invention in asolution or gel form were provided to patients having comedongenicand/or papulopustular lesions of acne. Each participating patient wasinstructed to apply topically the composition on the involved areas ofthe skin such as forehead, face and chest. Three times dailyadministration was continued for 6 to 12 weeks.

The degree and rate of improvement on ache lesions were clinicallyevaluated. It was found that acne lesions consisting mainly of comedonesimproved substantially after 6 to 8 weeks of topical administration withthe amphoteric or the pseudoamphoteric composition containing an alphahydroxyacid or the related compound. The time for complete clearing ofcomedongenic acne treated with the amphoteric or pseudoamphotericcomposition of the instant invention varied from 6 to 12 weeks.

As a topical treatment for papulopustular and/or pustular acne theamphoteric or pseudoamphoteric composition containing an alphahydroxyacid or the related compound may incorporate in addition anantiacne agent. The antiacne agents include antibiotics such aserythromycin, tetracycline, clindamycin, meclocycline and minocycline,and retinoids such as retinoic acid. Such combination compositions havebeen found to be therapeutically more effective for topical treatment ofsevere acne.

7. Age Spots

Many small and large discolored lesions, commonly called age spots onthe face and the back of the hands are benign keratoses, if they are notvariants of actinic keratoses. Very few of such age spots are truelentigines, therefore alpha hydroxyacids and the related compounds maybe effective in eradicating most age spots without concurrent use ofskin bleaching agents such as hydroquinone and monobenzone. However,additional beneficial effects have been found when a skin bleachingagent such as hydroquinone or monobenzone is also incorporated into thecompositions of the instant invention for age spots involving pigmentedlesions.

Amphoteric and pseudoamphoteric compositions containing alphahydroxyacids or the related compounds, with or without incorporation ofhydroquinone were provided to volunteer subjects and patients having agespot keratoses, melasma, lentigines and/or other pigmented lesions. Eachparticipating subject received two products, i.e., with or without theaddition of 2% hydroquinone to the amphoteric or pseudoamphotericcomposition containing an alpha hydroxyacid or the related compound.

The volunteer subjects and patients were instructed to apply topicallyone medication on one side of the body such as left side of the face oron the back of the left hand, and the other medication on the other sideof the body such as on right side of the face or on the back of theright hand. Specific instructions were given to the participatingsubjects that the medications were applied three times daily to thelesions of age spot keratoses, melasmas, lentigines and/or otherpigmented lesions. Clinical photos were taken of participating subjectsbefore the initiation of the topical treatment and every 4 weeks duringthe course of treatment.

At the end of 4 to 8 weeks, improvement of age spot keratoses wasclinically discernible. After 4 to 6 months of topical treatment,substantial improvement of age spot keratoses occurred in the majorityof subjects tested. Complete eradication of age spot keratoses occurredafter 6 to 9 months of topical administration with the amphoteric orpseudoamphoteric compositions of the instant inventions.

Amphoteric or Pseudoamphoteric compositions containing both an alphahydroxyacid or the related compound and hydroquinone were judged to bemore effective in eradicating pigmented age spots, melasma, lentiginesand other pigmented lesions.

The alpha hydroxyacids and the related compounds which have been foundto be therapeutically effective for age spots with or withoutcombination with hydroquinone include glycolic acid, lactic acid,methyllactic acid, mandelic acid, pyruvic acid, methyl pyruvate, ethylpyruvate, benzilic acid, gluconolactone, malic acid, tartaric acid,citric acid and tropic acid. For flat or slightly elevated seborrheickeratoses on the face and/or the back of the body, amphoteric orpseudoamphoteric compositions containing higher concentrations of alphahydroxyacids or the related compounds have been found to be effective ineradicating such lesions.

Actinic keratoses may be successfully treated with amphoteric orPseudoamphoteric compositions containing alpha hydroxyacids or therelated compounds in combination with an antimetabolite agent such as5-fluorouracil.

8. Warts.

Eradications of common warts by topical application of amphoteric orpseudoamphoteric compositions require higher than usual concentrationsof alpha hydroxyacids or the related compounds in the formulations. Theamphoteric or pseudoamphoteric compositions were formulated as a liquidor light gel form, and dispensed usually as 0.5-1 ml aliquots in smallvials.

Topical applications were made discreetly to wart lesions by adultpatients or by responsible adult family members. For ordinary usualwarts of hands, fingers, palms and soles topical applications were made2 to 4 times daily, and were continued for 2 to 6 weeks. Generally, theoverlying stratum corneum of the wart lesion change in appearance afterseveral weeks topical application of the composition. In most cases, thewart lesion simply fell off. The skin then healed normally withoutforming any scars.

We have also found that when a dermatologic agent such as 5-fluorouracilis incorporated into the amphoteric or pseudoamphoteric compositionscontaining alpha hydroxyacids or the related compounds, the medicationshave been very effective for topical treatment of warts without usinghigher concentrations of alpha hydroxyacids or the related compounds.

The alpha hydroxyacids and the related compounds which have been foundto be therapeutically effective for topical treatment of warts with orwithout incorporation of 5-fluorouracil include glycolic acid, lacticacid, pyruvic acid, ethyl pyruvate, methyl pyruvate and mandelic acid.

Topical formulations and compositions containing specific alphahydroxyacids, alpha ketoacids or the related compounds at full strengthsor high to intermediate concentrations prepared according to Examples 54and 55, without utilizing amphoteric or pseudoamphoteric systems, havealso been tested for ordinary warts of the hands, fingers, palms andsoles. Participating patients have been advised to apply a small drop ofthe medication with a toothpick or a fine caliber brush to the center ofa wart lesion only. Prescirbed applications have been 3 to 6 timesdaily, and are continued until the patient feels pain.

For the more rough-surfaced wart, the duration of application has beenas short as one or a few days. For lesions with more compact, lesspermeable stratum corneum, the time to experience gpain has been longer.Frequency and duration of applications have been modified according toother clinical responses and reactions of lesions, and the patient orresponsible family member is instructed accordingly.

For example, some clinical manifestations other than pain have also beenused as a signal to interrupt application. These manifestations haveincluded distinct blanching of the lesions or distinct peripheralerythema. Very often, discomfort is the usual signal of clinicalreactions.

Generally, the overlying stratum corneum of the wart lesions becameloose, and the whole wart lesion simply fell off. The skin then healednormally without forming any scars.

9. Athlete's Foot and Nail Infections

Amphoteric and pseudoamphoteric compositions containing both anantifungal agent and one of the alpha hydroxyacids or the relatedcompounds were provided to patients having frequent recurrence of fungalinfections involving the foot. The antifungal agents includeclotrimazole, miconazole, ketoconazole and griseofulvin. When both feetbut not toe nails were involved in the infection, the patients wereinstructed to apply topically the compositions of the instant inventionon the left foot, and a brand-name antifungal product on the right foot.Three times daily applications were continued for one to four weeks. Thedegree and rate of improvement on skin lesions were clinicallyevaluated, and comparison was made one side of the body against theother. It was found that the skin lesions improved much faster with theamphoteric or pseudoamphoteric compositions containing both theantifungal agent and the alpha hydroxyacid or the related compound. Thealpha hydroxyacids or the related compounds seemed to enhance theefficacies of the antifungal agents, and also to eliminate thediscomforts such as itching, tingling, burning and irritation due tofungal infections. When toe nails were not involved the infected skingenerally healed within one to two weeks from topical application of theamphoteric or pseudoamphoteric composition containing both an antifungalagent and an alpha hydroxyacid or the related compound.

Fungal infections of the nails are very difficult to treat, becauseantifungal products to date are not therapeutically effective fortopical treatment of nails. One of the reasons is that most antifungaldrugs have not been formulated as bioavailable forms in the commercialproducts. When tow nails were involved in the infections, patients wereprovided with amphoteric or pseudoamphoteric compositions containing incombination an antifungal agent and an alpha hydro-xyacid or an alphaketoacid at higher concentrations ranging from 20 to 99%, dispensed as1-2 ml aliquots in small vials. The patients were instructed to applytopically the compositions discreetly to the infected nail surface bymeans of a fine calibre paint brush. the technique was the same as forapplication of nail polish, that is careful avoidance of contact withlateral nail folds or any peri-ungual skin. Once or twice dailyapplications were continued for 2 to 8 weeks.

As mentioned above, while brand-name antifungal products are usually noteffective against fungus infections within or underneath the nail, itwas found that the amphoteric or pseudoamphoteric compositionscontaining an antifungal agent and an alpha hydroxyacid or alphaketoacid were therapeutically effective in eradicating fungal infectionsof the nails. Such treatment may cause in some instances the treatednail plate to become loose and eventually fell off from the nail bed.This happened quite naturally without any feeling of pain nor bleeding,and the skin lesion healed quickly with normal growth of a new nail.

10. Wrinkles

Wrinkles of skin may be due to natural aging and/or sun damage. Mostfine wrinkles on the face are due to natural or innate aging, whilecoarse wrinkles on the face are the consequence of actinic or sundamage. Although the real mechanism of wrinkles formation in the skin isstill unknown, it has been shown that visible fine wrinkles are due todiminution in the number and diameter of elastic fibers in the papillarydermis, and also due to atrophy of dermis as well as reduction insubcutaneous adipose tissue. Histopathology and electron microscopystudies indicate that coarse wrinkles are due to excessive deposition ofabnormal elastic materials in the upper dermis and thickening of theskin. At present there are no commercial products which have been foundto be therapeutically effective for topical eradication of wrinkles,although retinoic acid (tretinoin) has been shown to be beneficial forsun damaged skin.

In order to determine whether the amphoteric or pseudoamphotericcomposition containing the alpha hydroxyacids, alpha ketoacids or therelated compounds are therapeutically effective for wrinkles, patientsand volunteer subjects participated in this study. The participants wereinstructed to apply the formulations of the instant invention twicedaily on areas of facial wrinkles for 4 to 12 months. All participantswere told to avoid sun exposure, and to use sunscreen products ifexposure to sunlight was unavoidable. Photographs of each side of theface for each participant were taken at the beginning of the study andrepeated at one to three-month intervals. The participants were askednot to wear any facial make-up at the time of each office visit.Standardized photographic conditions were used including the use of samelot of photographic film, the same light source at two feet from theface, aimed at a locus on the frontal aspect of each cheek. Each timephotographs were taken with camera aimed perpendicular to the cheek. Atthe end of study twenty two participants had been entered into the studyfor at least four months. Clinical evaluations and review of photographshave revealed substantial reductions in facial wrinkles of the temporalregion and cheek area on at least one side of the face in eighteencases. Degree of improvement and reduction in wrinkles has beenevaluated and determined to be mild to moderate in six participants butvery substantial in twelve participants.

The alpha hydroxyacids, alpha ketoacids and other related compoundsincluding their lactone forms which may be incorporated into theamphoteric and pseudoamphoteric compositions for cosmetic conditions anddermatologic disorders such as dry skin, ache, age spots, keratoses,warts and skin wrinkles or in combination with other dermatologic agentsto enhance therapeutic effects include the following:

(1) Alkyl Alpha Hydroxyacids

2-Hydroxyethanoic acid (Glycolic acid), Hydroxypropanoic acid (Lacticacid), 2-Methyl hydroxypropanoic acid (Methyllactic acid),Hydroxybutanoic acid, 2-Hydroxypentanoic acid, Hydroxyhexanoic acid,2-Hydroxyheptanoic acid, Hydroxyoctanoic acid, 2-Hydroxynonanoic acid,Hydroxydecanoic acid, 2-Hydroxyundecanoic acid, Hydroxydodecanoic acid(Alpha hydroxylauric acid), 2-Hydroxytetradecanoic acid (Alphahydroxymyristic acid), 2-Hydroxyhexadecanoic acid (Alpha hydroxypalmiticacid), 2-Hydroxyoctadecanoic acid (Alpha hydroxystearic acid) ,2-Hydroxyeicosanoic acid (Alpha hydroxyarachidonic acid).

(2) Aralkyl And Aryl Alpha Hydroxyacids

2-Phenyl 2-hydroxyethanoic acid (Mandelic acid), 2,2-Diphenyl2-hydroxyethanoic acid (Benzilic acid), 3-Phenyl 2-hydroxypropanoic acid(Phenyllactic acid), 2-Phenyl 2 -methyl 2 -hydroxyethanoic acid(Atrolactic acid), 2-(4'-Hydroxyphenyl) 2-hydroxyethanoic acid,2-(4'-Clorophenyl) 2-hydroxyethanoic acid,2-(3'-Hydroxy-4'-methoxyphenyl) 2-hydroxyethanoic acid, 2-(4'-Hydroxy-3'-methoxyphenyl) 2-hydroxyethanoic acid, 3-(2'-Hydroxyphenyl)2-hydroxypropanoic acid, 3-(4'-Hydroxyphenyl) 2-hydroxypropanoic acid,2-(3',4'-Dihydroxyphenyl) 2-hydroxyethanoic acid.

(3) Polyhydroxy Alpha Hydroxyacids

2,3-Dihydroxypropanoic acid (Glyceric acid), 2,3,4-Trihydroxybutanoicacid (Isomers; erythronic acid, threonic acid),2,3,4,5-Tetrahydroxypentanoic acid (Isomers; ribonic acid, arabinoicacid, xylonic acid, lyxonic acid), 2,3,4,5,6-Pentahydroxyhexanoic acid(Isomers; aldonic acid, altronic acid, gluconic acid, mannoic acid,gulonic acid, idonic acid, galactonic acid, talonic acid),.2,3,4,5,6,7-Hexahydroxyheptanoic acid (Isomers; glucoheptonic acid,galactoheptonic acid, etc.)

(4) Polycarboxylic Alpha Hydroxyacids

2-Hydroxypropane-1,3-dioic acid (Tartronic acid),2-Hydroxybutane-1,4-dioic acid (Malic acid),2,3-Dihydroxybutane-1,4-dioic acid (Tartaric acid),2-Hydroxy-2-carboxypentane-1,5-dioic acid (Citric acid),2,3,4,5-Tetrahydroxyhexane-1,6-dioic acid (Isomers; saccharic acid,mucic acid, etc.)

(5) Alpha Hydroxyacid Related Compounds

Ascorbic acid, quinic acid, isocitric acid, tropic acid, 3-chlorolacticacid, trethocanic acid, cerebronic acid, citramalic acid, agaricic acid,2-hydroxynervonic acid and aleuritic acid.

(6) Alpha Ketoacids And Related Compounds

2-Ketoethanoic acid (Glyoxylic acid), Methyl 2-ketoethanoate,2-Ketopropanoic acid (Pyruvic acid), Methyl 2-ketopropanoate (Methylpyruvate), Ethyl, 2-ketopropanoate (Ethyl pyruvate), Propyl2-ketopropanoate (Propyl pyruvate), 2-Phenyl-2-ketoethanoic acid(Benzoylformic acid), Methyl 2-phenyl-2-ketoethanoate (Methylbenzoylformate), Ethyl 2-phenyl-2-ketoethanoate (Ethyl benzoylformate),3-Phenyl-2-ketopropanoic acid (Phenylpyruvic acid), Methyl3-phenyl-2-ketopropanoate (Ethyl phenylpyruvate), 2-Ketobutanoic acid,2-Ketopentanoic acid, 2-Ketohexanoic acid, 2-Ketoheptanoic acid,Ketooctanoic acid, 2-Ketododecanoic acid, Methyl 2-ketooctanoate

The amphoteric and pseudoamphoteric compounds which may be incorporatedinto the compositions of the instant invention for cosmetic anddermatologic conditions include amino acids, peptides, polypeptides,proteins and the like compounds such as creatinine and creatine.

The dimeric and polymeric forms of alpha hydroxyacids and the relatedcomopounds which may-be incorporated into the compositions of theinstant invention include acyclic esters and cyclic ester; for example,glycolyl glycollate, lactyl lactate, glycolide, lactide, polyglycolicacid and polylactic acid.

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The presentembodiments are therefore to be considered in all respects asillustrative and not restrictive, the scope of the invention beingindicated by the appended claims and all changes which come within themeaning and equivalency of the claims are therefore intended to beembraced therein.

We claim:
 1. Method of visibly reducing a human skin wrinkle comprisingtopically applying to said wrinkle a composition comprising glucuronicacid or a topically effective salt thereof, or glucuronolactone in anamount and for a period of time sufficient to visibly reduce saidwrinkle.
 2. The method according to claim 1, wherein said glucuronicacid is in the form of a topically effective salt.
 3. The methodaccording to claim 1, wherein said method utilizes glucuronolactone. 4.The method according to claim 1, wherein said composition is appliedperiodically for a period of time sufficient to achieve at least avisibly mild to moderate reduction of said wrinkle.
 5. The methodaccording to claim 1, wherein said composition is applied periodicallyfor a period of time sufficient to achieve at least a substantialreduction of said wrinkle.
 6. The method according to claim 1, whereinsaid period of time is at least two months.
 7. The method according toclaim 1, wherein said period of time is at least three months.
 8. Themethod according to claim 1, wherein said period of time is at leastfour months.
 9. The method according to claim 1, wherein said topicalapplication is on a daily basis.
 10. The method according to claim 1,wherein said wrinkle is a fine wrinkle.
 11. The method according toclaim 1, wherein said wrinkle is a coarse wrinkle.
 12. The methodaccording to claim 1, wherein said wrinkle is the result of actinic orsun damage.
 13. The method according to claim 1, wherein said glucuronicacid or topically effective salt thereof or glucuronolactone is theprincipal ingredient responsible for said reduction.
 14. A method forreversing or retarding the effect of aging on human facial skin, saideffect being a change in the dermis that results from natural or mateaging or exposure to actinic radiation,said, change in the dermisselected from the group consisting of a diminution in the number and,diameter of elastic fibers in the papillary dermis, atrophy of thedermis, reduction in subcutaneous adipose tissue and deposition ofabnormal elastic materials in the upper dermis, said method comprisingtopically applying to said facial skin a composition comprisingglucuronic acid or a topically effective salt thereof, orglucuronolactone in an amount and for a period of time sufficient toreverse or prevent said change in the dermis, wherein said glucuronicacid or a topically effective salt thereof, or glucuronolactone is theprincipal ingredient responsible for said reversing or retarding. 15.The method according to claim 14, wherein said glucuronic acid is in theform of a free acid or a salt.
 16. The method according to claim 14,wherein said period of time is at least three months.
 17. The methodaccording to claim 14, wherein said period of time is at least fourmonths.
 18. The method according to claim 14, wherein said topicalapplication is on a daily basis.
 19. The method according to claim 14,wherein said change in the dermis results from natural or innate aging.20. The method according to claim 14, wherein said change in the dermisresults from exposure to actinic radiation.